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Sample records for human msh2 locus

  1. Interdependence of DNA mismatch repair proteins MLH1 and MSH2 in apoptosis in human colorectal carcinoma cell lines.

    Science.gov (United States)

    Hassen, Samar; Ali, Akhtar A; Kilaparty, Surya P; Al-Anbaky, Qudes A; Majeed, Waqar; Boman, Bruce M; Fields, Jeremy Z; Ali, Nawab

    2016-01-01

    indicator of apoptosis, showed that MLH1 translocation only occurred in MMR proficient (SW480) cells upon induction of apoptosis further suggested a MSH2 dependent role of MLH1 in apoptosis. These data suggest a role of MLH1 in mediation of apoptosis in a MSH2-dependent manner. Taken together, our data supported an interdependence of mismatch repair proteins, particularly MLH1 and MSH2, in the mediation of apoptosis in human colorectal carcinoma cell lines.

  2. Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: An immunohistochemical study

    Science.gov (United States)

    Giaginis, Constantinos; Michailidi, Christina; Stolakis, Vasileios; Alexandrou, Paraskevi; Tsourouflis, Gerasimos; Klijanienko, Jerzy; Delladetsima, Ioanna; Theocharis, Stamatios

    2011-01-01

    Summary Background DNA repair is a major defense mechanism, which contributes to the maintenance of genetic sequence, and minimizes cell death, mutation rates, replication errors, DNA damage persistence and genomic instability. Alterations in the expression levels of proteins participating in DNA repair mechanisms have been associated with several aspects of cancer biology. The present study aimed to evaluate the clinical significance of DNA repair proteins MSH2, MLH1 and MGMT in benign and malignant thyroid lesions. Material/Methods MSH2, MLH1 and MGMT protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 90 patients with benign and malignant lesions. Results The expression levels of MLH1 was significantly upregulated in cases with malignant compared to those with benign thyroid lesions (p=0.038). The expression levels of MGMT was significantly downregulated in malignant compared to benign thyroid lesions (p=0.001). Similar associations for both MLH1 and MGMT between cases with papillary carcinoma and hyperplastic nodules were also noted (p=0.014 and p=0.026, respectively). In the subgroup of malignant thyroid lesions, MSH2 downregulation was significantly associated with larger tumor size (p=0.031), while MLH1 upregulation was significantly associated with the presence of lymphatic and vascular invasion (p=0.006 and p=0.002, respectively). Conclusions Alterations in the mismatch repair proteins MSH2 and MLH1 and the direct repair protein MGMT may result from tumor development and/or progression. Further studies are recommended to draw definite conclusions on the clinical significance of DNA repair proteins in thyroid neoplasia. PMID:21358597

  3. Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma.

    Science.gov (United States)

    Pećina-Šlaus, Nives; Kafka, Anja; Bukovac, Anja; Vladušić, Tomislav; Tomas, Davor; Hrašćan, Reno

    2017-07-01

    Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ 2  = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.

  4. Functional analysis of HNPCC-related missense mutations in MSH2

    Energy Technology Data Exchange (ETDEWEB)

    Luetzen, Anne [Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde (Denmark); Wind, Niels de; Georgijevic, Dubravka [Department of Toxicogenetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden (Netherlands); Nielsen, Finn Cilius [Department of Clinical Biochemistry, Rigshospitalet, DK-2100 Copenhagen (Denmark); Rasmussen, Lene Juel [Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde (Denmark)], E-mail: ljr@ruc.dk

    2008-10-14

    Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in the human DNA mismatch repair (MMR) genes, most frequently MSH2 and MLH1. The majority of HNPCC mutations cause truncations and thus loss of function of the affected polypeptide. However, a significant proportion of MMR mutations found in HNPCC patients are single amino acid substitutions and the functional consequences of many of these mutations in DNA repair are unclear. We have examined the consequences of seven MSH2 missense mutations found in HNPCC families by testing the MSH2 mutant proteins in functional assays as well as by generating equivalent missense mutations in Escherichia coli MutS and analyzing the phenotypes of these mutants. Here we show that two mutant proteins, MSH2-P622L and MSH2-C697F confer multiple biochemical defects, namely in mismatch binding, in vivo interaction with MSH6 and EXO1, and in nuclear localization in the cell. Mutation G674R, located in the ATP-binding region of MSH2, appears to confer resistance to ATP-dependent mismatch release. Mutations D167H and H639R show reduced mismatch binding. Results of in vivo experiments in E. coli with MutS mutants show that one additional mutant, equivalent of MSH2-A834T that do not show any defects in MSH2 assays, is repair deficient. In conclusion, all mutant proteins (except for MSH2-A305T) have defects; either in mismatch binding, ATP-release, mismatch repair activity, subcellular localization or protein-protein interactions.

  5. Functional analysis of HNPCC-related missense mutations in MSH2

    International Nuclear Information System (INIS)

    Luetzen, Anne; Wind, Niels de; Georgijevic, Dubravka; Nielsen, Finn Cilius; Rasmussen, Lene Juel

    2008-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in the human DNA mismatch repair (MMR) genes, most frequently MSH2 and MLH1. The majority of HNPCC mutations cause truncations and thus loss of function of the affected polypeptide. However, a significant proportion of MMR mutations found in HNPCC patients are single amino acid substitutions and the functional consequences of many of these mutations in DNA repair are unclear. We have examined the consequences of seven MSH2 missense mutations found in HNPCC families by testing the MSH2 mutant proteins in functional assays as well as by generating equivalent missense mutations in Escherichia coli MutS and analyzing the phenotypes of these mutants. Here we show that two mutant proteins, MSH2-P622L and MSH2-C697F confer multiple biochemical defects, namely in mismatch binding, in vivo interaction with MSH6 and EXO1, and in nuclear localization in the cell. Mutation G674R, located in the ATP-binding region of MSH2, appears to confer resistance to ATP-dependent mismatch release. Mutations D167H and H639R show reduced mismatch binding. Results of in vivo experiments in E. coli with MutS mutants show that one additional mutant, equivalent of MSH2-A834T that do not show any defects in MSH2 assays, is repair deficient. In conclusion, all mutant proteins (except for MSH2-A305T) have defects; either in mismatch binding, ATP-release, mismatch repair activity, subcellular localization or protein-protein interactions

  6. (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition.

    Science.gov (United States)

    Owen, Barbara A L; Yang, Zungyoon; Lai, Maoyi; Gajec, Maciej; Gajek, Maciez; Badger, John D; Hayes, Jeffrey J; Edelmann, Winfried; Kucherlapati, Raju; Wilson, Teresa M; McMurray, Cynthia T

    2005-08-01

    Cells have evolved sophisticated DNA repair systems to correct damaged DNA. However, the human DNA mismatch repair protein Msh2-Msh3 is involved in the process of trinucleotide (CNG) DNA expansion rather than repair. Using purified protein and synthetic DNA substrates, we show that Msh2-Msh3 binds to CAG-hairpin DNA, a prime candidate for an expansion intermediate. CAG-hairpin binding inhibits the ATPase activity of Msh2-Msh3 and alters both nucleotide (ADP and ATP) affinity and binding interfaces between protein and DNA. These changes in Msh2-Msh3 function depend on the presence of A.A mispaired bases in the stem of the hairpin and on the hairpin DNA structure per se. These studies identify critical functional defects in the Msh2-Msh3-CAG hairpin complex that could misdirect the DNA repair process.

  7. Functional analysis of HNPCC-related missense mutations in MSH2

    DEFF Research Database (Denmark)

    Lützen, Anne; de Wind, Niels; Georgijevic, Dubravka

    2008-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in the human DNA mismatch repair (MMR) genes, most frequently MSH2 and MLH1. The majority of HNPCC mutations cause truncations and thus loss of function of the affected polypeptide. However, a significant...

  8. Cancer risks for MLH1 and MSH2 mutation carriers

    OpenAIRE

    Dowty, James G.; Win, Aung K.; Buchanan, Daniel D.; Lindor, Noralane M.; Macrae, Finlay A.; Clendenning, Mark; Antill, Yoland C.; Thibodeau, Stephen N.; Casey, Graham; Gallinger, Steve; Le Marchand, Loic; Newcomb, Polly A.; Haile, Robert W.; Young, Graeme P.; James, Paul A.

    2013-01-01

    We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC) and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks to age 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, ...

  9. Translocations affecting human immunoglobulin heavy chain locus

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    Sklyar I. V.

    2014-03-01

    Full Text Available Translocations involving human immunoglobulin heavy chain (IGH locus are implicated in different leukaemias and lymphomas, including multiple myeloma, mantle cell lymphoma, Burkitt’s lymphoma and diffuse large B cell lymphoma. We have analysed published data and identified eleven breakpoint cluster regions (bcr related to these cancers within the IgH locus. These ~1 kbp bcrs are specific for one or several types of blood cancer. Our findings could help devise PCR-based assays to detect cancer-related translocations, to identify the mechanisms of translocations and to help in the research of potential translocation partners of the immunoglobulin locus at different stages of B-cell differentiation.

  10. NPM-ALK mediates phosphorylation of MSH2 at tyrosine 238, creating a functional deficiency in MSH2 and the loss of mismatch repair

    International Nuclear Information System (INIS)

    Bone, K M; Wang, P; Wu, F; Wu, C; Li, L; Bacani, J T; Andrew, S E; Lai, R

    2015-01-01

    The vast majority of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ALCL) tumors express the characteristic oncogenic fusion protein NPM-ALK, which mediates tumorigenesis by exerting its constitutive tyrosine kinase activity on various substrates. We recently identified MSH2, a protein central to DNA mismatch repair (MMR), as a novel binding partner and phosphorylation substrate of NPM-ALK. Here, using liquid chromatography–mass spectrometry, we report for the first time that MSH2 is phosphorylated by NPM-ALK at a specific residue, tyrosine 238. Using GP293 cells transfected with NPM-ALK, we confirmed that the MSH2 Y238F mutant is not tyrosine phosphorylated. Furthermore, transfection of MSH2 Y238F into these cells substantially decreased the tyrosine phosphorylation of endogenous MSH2. Importantly, gene transfection of MSH2 Y238F abrogated the binding of NPM-ALK with endogenous MSH2, re-established the dimerization of MSH2:MSH6 and restored the sensitivity to DNA mismatch-inducing drugs, indicative of MMR return. Parallel findings were observed in two ALK+ALCL cell lines, Karpas 299 and SUP-M2. In addition, we found that enforced expression of MSH2 Y238F into ALK+ALCL cells alone was sufficient to induce spontaneous apoptosis. In conclusion, our findings have identified NPM-ALK-induced phosphorylation of MSH2 at Y238 as a crucial event in suppressing MMR. Our studies have provided novel insights into the mechanism by which oncogenic tyrosine kinases disrupt MMR

  11. The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline

    International Nuclear Information System (INIS)

    Burr, Karen L-A.; Duyn-Goedhart, Annemarie van; Hickenbotham, Peter; Monger, Karen; Buul, Paul P.W. van; Dubrova, Yuri E.

    2007-01-01

    Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of mismatch repair deficient Msh2 knock-out mice. Spontaneous mutation rates in homozygous Msh2 -/- males were significantly higher than those in isogenic wild-type (Msh2 +/+ ) and heterozygous (Msh2 +/- ) mice. In contrast, the irradiated Msh2 -/- mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated Msh2 +/+ and Msh2 +/- animals. Considering these data and the results of other publications, we propose that the Msh2-deficient mice possess a mutator phenotype in their germline and somatic tissues while the loss of a single Msh2 allele does not affect the stability of heterozygotes

  12. Gene expression of the mismatch repair gene MSH2 in primary colorectal cancer

    DEFF Research Database (Denmark)

    Jensen, Lars Henrik; Kuramochi, Hidekazu; Crüger, Dorthe Gylling

    2011-01-01

    promoter was only detected in 14 samples and only at a low level with no correlation to gene expression. MSH2 gene expression was not a prognostic factor for overall survival in univariate or multivariate analysis. The gene expression of MSH2 is a potential quantitative marker ready for further clinical...

  13. Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis.

    Science.gov (United States)

    Ehsani, Laleh; Osunkoya, Adeboye O

    2014-09-01

    In this study, we investigated microsatellite instability in urothelial carcinoma of the renal pelvis by lack of immunohistochemical staining for MLH1 and MSH2. The study included 44 cases of urothelial carcinoma of the renal pelvis obtained from radical nephroureterectomy specimens at our institution. We evaluated the loss of nuclear immunohistochemical staining of MLH1 and MSH2. Eight of 44 (18 %) patients had negative MLH1 expression and 25/44 (57 %) patients had negative MSH2 expression. Six of 8 (75 %) patients with negative MLH1 expression were male and 2/8 (25 %) patients were female. Nineteen of 25 (75 %) patients with negative MSH2 expression were male, and 6/25 (24 %) patients were female. Seven of 8 (88 %) cases with negative MLH1 expression were high-grade urothelial carcinoma, and 21/25 (84 %) cases with negative MSH2 expression were high-grade urothelial carcinoma. Twenty-one of 44 (48 %) cases had an inverted growth pattern, of which 3/21 (14 %) cases had negative MLH1 expression and 14/21 (67 %) cases had negative MSH2 expression. Our study showed that microsatellite instability based on negative expression of MLH1 and MSH2 was more common in male patients with high-grade urothelial carcinoma. There is a strong correlation between inverted growth pattern and negative MSH2 expression. Microsatellite instability testing should be performed in patients with upper urinary tract carcinoma and may have prognostic value.

  14. Mapping of the methylation pattern of the hMSH2 promoter in colon cancer, using bisulfite genomic sequencing

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    Zhang Hua

    2006-08-01

    Full Text Available Abstract The detailed methylation status of CpG sites in the promoter region of hMSH2 gene has yet not to be reported. We have mapped the complete methylation status of the hMSH2 promoter, a region that contains 75 CpG sites, using bisulfite genomic sequencing in 60 primary colorectal cancers. And the expression of hMSH2 was detected by immunohistochemistry. The hypermethylation of hMSH2 was detected in 18.33% (11/60 of tumor tissues. The protein of hMSH2 was detected in 41.67% (25/60 of tumor tissues. No hypermethylation of hMSH2 was detected in normal tissues. The protein of hMSH2 was detected in all normal tissues. Our study demonstrated that hMSH2 hypermethylation and protein expression were associated with the development of colorectal cancer.

  15. Combined deficiency of MSH2 and Sμ region abolishes class switch recombination.

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    Leduc, Claire; Haddad, Dania; Laviolette-Malirat, Nathalie; Nguyen Huu, Ngoc-Sa; Khamlichi, Ahmed Amine

    2010-10-01

    Class switch recombination (CSR) is mediated by G-rich tandem repeated sequences termed switch regions. Transcription of switch regions generates single-stranded R loops that provide substrates for activation-induced cytidine deaminase. Mice deficient in MSH2 have a mild defect in CSR and analysis of their switch junctions has led to a model in which MSH2 is more critical for switch recombination events outside than within the tandem repeats. It is also known that deletion of the whole Sμ region severely impairs but does not abrogate CSR despite the lack of detectable R loops. Here, we demonstrate that deficiency of both MSH2 and the Sμ region completely abolishes CSR and that the abrogation occurs at the genomic level. This finding further supports the crucial role of MSH2 outside the tandem repeats. It also indicates that during CSR, MSH2 has access to activation-induced cytidine deaminase targets in R-loop-deficient Iμ-Cμ sequences rarely used in CSR, suggesting an MSH2-dependent DNA processing activity at the Iμ exon that may decrease with transcription elongation across the Sμ region.

  16. Strengthening Locus Standi in Human Rights Litigation in Zimbabwe ...

    African Journals Online (AJOL)

    MJM Venter

    2016-05-30

    May 30, 2016 ... approach is likely to impact on the right to access to justice and human rights protection. 2. Locus standi ... Committee on Economic, Social and Cultural Rights General Comment 9: The. Domestic .... animosity towards an accused, in bad faith and without any warrant, were to rule that the question raised by ...

  17. Mutation at the Human D1S80 Minisatellite Locus

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    Kuppareddi Balamurugan

    2012-01-01

    Full Text Available Little is known about the general biology of minisatellites. The purpose of this study is to examine repeat mutations from the D1S80 minisatellite locus by sequence analysis to elucidate the mutational process at this locus. This is a highly polymorphic minisatellite locus, located in the subtelomeric region of chromosome 1. We have analyzed 90,000 human germline transmission events and found seven (7 mutations at this locus. The D1S80 alleles of the parentage trio, the child, mother, and the alleged father were sequenced and the origin of the mutation was determined. Using American Association of Blood Banks (AABB guidelines, we found a male mutation rate of 1.04×10-4 and a female mutation rate of 5.18×10-5 with an overall mutation rate of approximately 7.77×10-5. Also, in this study, we found that the identified mutations are in close proximity to the center of the repeat array rather than at the ends of the repeat array. Several studies have examined the mutational mechanisms of the minisatellites according to infinite allele model (IAM and the one-step stepwise mutation model (SMM. In this study, we found that this locus fits into the one-step mutation model (SMM mechanism in six out of seven instances similar to STR loci.

  18. Predictive value of MSH2 gene expression in colorectal cancer treated with capecitabine

    DEFF Research Database (Denmark)

    Jensen, Lars H; Danenberg, Kathleen D; Danenberg, Peter V

    2007-01-01

    was associated with a hazard ratio of 0.5 (95% confidence interval, 0.23-1.11; P = 0.083) in survival analysis. CONCLUSION: The higher gene expression of MSH2 in responders and the trend for predicting overall survival indicates a predictive value of this marker in the treatment of advanced CRC with capecitabine.......PURPOSE: The objective of the present study was to evaluate the gene expression of the DNA mismatch repair gene MSH2 as a predictive marker in advanced colorectal cancer (CRC) treated with first-line capecitabine. PATIENTS AND METHODS: Microdissection of paraffin-embedded tumor tissue, RNA...

  19. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations

    DEFF Research Database (Denmark)

    Joost, Patrick; Therkildsen, Christina; Dominguez-Valentin, Mev

    2015-01-01

    and microsatellite instability in 23% of the tumors. Mutations in MSH2 were overrepresented (73%), and MSH2 mutation carriers were at a significantly increased risk of developing urinary tract cancer compared with individuals with mutations in MLH1 or MSH6. CONCLUSION: Cancers of the upper urinary tract...

  20. Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.

    Science.gov (United States)

    Stark, Andreas M; Doukas, Alexander; Hugo, Heinz-Herrmann; Hedderich, Jürgen; Hattermann, Kirsten; Maximilian Mehdorn, H; Held-Feindt, Janka

    2015-02-01

    Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma. Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival. (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (PMLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation. Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.

  1. Repair genes expression profile of MLH1, MSH2 and ATM in the normal oral mucosa of chronic smokers.

    Science.gov (United States)

    Alves, Mônica Ghislaine Oliveira; Carta, Celina Faig Lima; de Barros, Patrícia Pimentel; Issa, Jaqueline Scholz; Nunes, Fábio Daumas; Almeida, Janete Dias

    2017-01-01

    The aim of this study was to evaluate the effect of chronic smoking on the expression profile of the repair genes MLH1, MSH2 and ATM in the normal oral mucosa of chronic smokers and never smokers. The sample consisted of thirty exfoliative cytology smears per group obtained from Smokers and Never Smokers. Total RNA was extracted and expression of the MLH1, MSH2 and ATM genes were evaluated by quantitative real-time and immunocytochemistry. The gene and protein expression data were correlated to the clinical data. Gene expression was analyzed statistically using the Student t-test and Pearson's correlation coefficient, with pMLH1, MSH2 and ATM genes were downregulated in the smoking group compared to the control with significant values for MLH1 (p=0.006), MSH2 (p=0.0001) and ATM (p=0.0001). Immunocytochemical staining for anti-MLH1, anti-MSH2 and anti-ATM was negative in Never Smokers; in Smokers it was rarely positive. No significant correlation was observed among the expression of MLH1, MSH2, ATM and age, number of cigarettes consumed per day, time of smoking during life, smoking history or levels of CO in expired air. The expression of genes and proteins related to DNA repair mechanism MLH1, MSH2 and ATM in the normal oral mucosa of chronic smokers was reduced. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Excess of extracolonic non-endometrial multiple primary cancers in MSH2 germline mutation carriers over MLH1.

    Science.gov (United States)

    Lin-Hurtubise, Kevin M; Yheulon, Christopher G; Gagliano, Ronald A; Lynch, Henry T

    2013-12-01

    The lynch syndrome (LS) tumor spectrum involves colorectal cancer (CRC), endometrial cancer (EC), and less frequently various extracolonic non-endometrial cancers (non-EC). The organ-specific survival rates of these patients are well defined, however, the collective survival of all-cancers combined (CRC + EC + non-EC) are unclear. Fifty-two MSH2 patients and 68 MLH1 patients were followed for a median of 6.3 years after diagnosis of first cancer, regardless of type. The proportions of CRC only, EC, non-EC, and multiple primary cancers were compared between the two genotypes. Kaplan-Meier curves were developed for survival comparisons. MSH2 patients present less frequently with only CRC (37% MSH2, 62% MLH1, P = 0.0096), manifest more multiple primary cancers (38% MSH2, 18% MLH1, P = 0.013), develop more extracolonic cancers (62% MSH2, 38% MLH1, P = 0.003), non-EC only cancers (46% MSH2, 24% MLH1, P = 0.028) and carry a greater risk for urinary tract cancer (UTC) (13.4% MSH2, 1.5% MLH1, P = 0.024). There was no difference in 10-year survival between the two groups (P = 0.4). The additional propensity for UTC in MSH2 carriers argues in favor of UTC screening in MSH2 individuals. Other types of cancer screening should be tailored to the expression history of the specific LS mutation. © 2013 Wiley Periodicals, Inc.

  3. Synchronous lung tumours in a patient with metachronous colorectal carcinoma and a germline MSH2 mutation.

    LENUS (Irish Health Repository)

    Canney, A

    2012-02-01

    Mutations of DNA mismatch repair genes are characterised by microsatellite instability and are implicated in carcinogenesis. This mutation susceptible phenotype has been extensively studied in patients with hereditary non-polyposis colon carcinoma, but little is known of the contribution of such mutations in other tumour types, particularly non-small-cell lung carcinoma. This report describes the occurrence of two synchronous lung tumours, one mimicking a metastatic colon carcinoma, in a male patient with a history of metachronous colonic carcinoma. Immunohistochemistry supported a pulmonary origin for both lesions. Mismatch repair protein immunohistochemistry showed loss of MSH2 and MSH6 expression in both colonic tumours and in one lung tumour showing enteric differentiation. Subsequent mutational analysis demonstrated a deleterious germline mutation of the MSH2 mismatch repair gene. The significance of these findings and the practical diagnostic difficulties encountered in this case are discussed.

  4. Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients

    DEFF Research Database (Denmark)

    Christensen, Lise Lotte; Kariola, Reetta; Korhonen, Mari K

    2009-01-01

    Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some...... of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity...

  5. Novel Mutations in MLH1 and MSH2 Genes in Mexican Patients with Lynch Syndrome

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    Jose Miguel Moreno-Ortiz

    2016-01-01

    Full Text Available Background. Lynch Syndrome (LS is characterized by germline mutations in the DNA mismatch repair (MMR genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC, and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del and c.1852_1853delinsGC (p.K618A in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel.

  6. A Mononucleotide Markers Panel to Identify hMLH1/hMSH2 Germline Mutations

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    M. Pedroni

    2007-01-01

    Full Text Available Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI. MSI is present in 85–90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as the “Bethesda panel”. Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites.

  7. Novel germline MSH2 mutation in lynch syndrome patient surviving multiple cancers

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    Janavicius Ramunas

    2012-01-01

    Full Text Available Abstract Lynch syndrome (LS individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers. We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear. In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up.

  8. Functional examination of MLH1, MSH2, and MSH6 intronic mutations identified in Danish colorectal cancer patients.

    Science.gov (United States)

    Petersen, Sanne M; Dandanell, Mette; Rasmussen, Lene J; Gerdes, Anne-Marie; Krogh, Lotte N; Bernstein, Inge; Okkels, Henrik; Wikman, Friedrik; Nielsen, Finn C; Hansen, Thomas V O

    2013-10-03

    Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomic rearrangements. However, a large number of mutations, including missense, silent, and intronic variants, are classified as variants of unknown clinical significance. Intronic MLH1, MSH2, or MSH6 variants were investigated using in silico prediction tools and mini-gene assay to asses the effect on splicing. We describe in silico and in vitro characterization of nine intronic MLH1, MSH2, or MSH6 mutations identified in Danish colorectal cancer patients, of which four mutations are novel. The analysis revealed aberrant splicing of five mutations (MLH1 c.588 + 5G > A, MLH1 c.677 + 3A > T, MLH1 c.1732-2A > T, MSH2 c.1276 + 1G > T, and MSH2 c.1662-2A > C), while four mutations had no effect on splicing compared to wild type (MLH1 c.117-34A > T, MLH1 c.1039-8 T > A, MSH2 c.2459-18delT, and MSH6 c.3439-16C > T). In conclusion, we classify five MLH1/MSH2 mutations as pathogenic, whereas four MLH1/MSH2/MSH6 mutations are classified as neutral. This study supports the notion that in silico prediction tools and mini-gene assays are important for the classification of intronic variants, and thereby crucial for the genetic counseling of patients and their family members.

  9. Identification of MSH2 inversion of exons 1-7 in clinical evaluation of families with suspected Lynch syndrome.

    Science.gov (United States)

    Mork, Maureen E; Rodriguez, Andrea; Taggart, Melissa W; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; Bannon, Sarah A; You, Y Nancy; Vilar, Eduardo

    2017-07-01

    Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining.

  10. Somatic cell genotoxicity at the glycophorin A locus in humans

    International Nuclear Information System (INIS)

    Jensen, R.H.; Grant, S.G.; Langlois, R.G.; Bigbee, W.L.

    1990-01-01

    We have developed an assay for detecting variant erythrocytes that occur as a result of in vivo allele loss at the glycophorin A (GPA) locus on chromosome 4 in humans. This gene codes for an erythroid- specific cell surface glycoprotein, and with our assay we are able to detect rare variant erythrocytes that have lost expression of one of the two GPA alleles. Two distinctly different variant cell types are detected with this assay. One variant cell type (called N OE) is hemizygous. Our assay also detects homozygous variant erythrocytes that have lost expression of the GPA(M) allele and express the GPA(N) allele at twice the heterozygous level. The results of this assay are an enumeration of the frequency of N OE and NN variant cell types for each individual analyzed. These variant cell frequencies provide a measure of the amount of somatic cell genotoxicity that has occurred at the GPA locus. Such genotoxicity could be the result of (1) reactions of toxic chemicals to which the individual has been exposed, or (2) high energy radiation effects on erythroid precursor cells, or (3) errors in DNA replication or repair in these cells of the bone marrow. Thus, the GPA-based variant cell frequency can serve as a biodosimeter that indicates the amount of genotoxic exposure each individual has received. Because two very different kinds of variant cells are enumerated, different kinds of genotoxicity should be distinguishable. Results of the GPA somatic genotoxicity assay may also provide valuable information for cancer-risk estimation on each individual. 16 refs

  11. Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer.

    Science.gov (United States)

    Sanguedolce, Francesca; Cormio, Antonella; Massenio, Paolo; Pedicillo, Maria C; Cagiano, Simona; Fortunato, Francesca; Calò, Beppe; Di Fino, Giuseppe; Carrieri, Giuseppe; Bufo, Pantaleo; Cormio, Luigi

    2018-04-01

    The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue. We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette-Guerin (BCG). HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS. Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.

  12. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.

    Science.gov (United States)

    Pritchard, Colin C; Morrissey, Colm; Kumar, Akash; Zhang, Xiaotun; Smith, Christina; Coleman, Ilsa; Salipante, Stephen J; Milbank, Jennifer; Yu, Ming; Grady, William M; Tait, Jonathan F; Corey, Eva; Vessella, Robert L; Walsh, Tom; Shendure, Jay; Nelson, Peter S

    2014-09-25

    A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the mechanisms of hypermutation in prostate cancer compared with other MSI-associated cancers.

  13. Molecular studies of deletions at the human steroid sulfatase locus

    International Nuclear Information System (INIS)

    Shapiro, L.J.; Yen, P.; Pomerantz, D.; Martin, E.; Rolewic, L.; Mohandas, T.

    1989-01-01

    The human steroid sulfatase gene (STS) is located on the distal X chromosome short arm close to the pseudoautosomal region but in a segment of DNA that is unique to the X chromosome. In contrast to most X chromosome-encoded genes, STS expression is not extinguished during the process of X chromosome inactivation. Deficiency of STS activity produced the syndrome of X chromosome-linked ichthyosis, which is one of the most common inborn errors of metabolism in man. Approximately 90% of STS - individuals have large deletions at the STS locus. The authors and others have found that the end points of such deletions are heterogeneous in their location. One recently ascertained subject was observed to have a 40-kilobase deletion that is entirely intragenic, permitting the cloning and sequencing of the deletion junction. Studies of this patient and of other X chromosome sequences in other subjects permit some insight into the mechanism(s) responsible for generating frequent deletions on the short arm of the X chromosome

  14. A locus for isolated cataract on human Xp.

    Science.gov (United States)

    Francis, P J; Berry, V; Hardcastle, A J; Maher, E R; Moore, A T; Bhattacharya, S S

    2002-02-01

    To genetically map the gene causing isolated X linked cataract in a large European pedigree. Using the patient registers at Birmingham Women's Hospital, UK, we identified and examined 23 members of a four generation family with nuclear cataract. Four of six affected males also had complex congenital heart disease. Pedigree data were collated and leucocyte DNA extracted from venous blood. Linkage analysis by PCR based microsatellite marker genotyping was used to identify the disease locus and mutations within candidate genes screened by direct sequencing. The disease locus was genetically refined to chromosome Xp22, within a 3 cM linkage interval flanked by markers DXS9902 and DXS999 (Zmax=3.64 at theta=0 for marker DXS8036). This is the first report of a locus for isolated inherited cataract on the X chromosome. The disease interval lies within the Nance-Horan locus suggesting allelic heterogeneity. The apparent association with congenital cardiac anomalies suggests a possible new oculocardiac syndrome.

  15. Specific locus mutagenesis of human mammary epithelial cells by ultraviolet radiation

    International Nuclear Information System (INIS)

    Eldridge, S.R.; Gould, M.N.

    1991-01-01

    Tissue and locus specificity of mutation induction was studied in human mammary epithelial cells (HMEC). Primary HMEC from normal tissue, and immortalized HMEC (184B5) derived from normal HMEC, were cultured under identical conditions and exposed to 10J/m 2 ultraviolet (UV) radiation (254 nm peak wavelength), which produced approximately 50% mean survival in all cell strains and lines tested. UV radiation was found to induce mutations at the Na + -K + ATPase locus as determined by ouabain-resistance in both normal and immortalized HMEC. Mutation frequencies measured in these cells following UV exposure were similar to those reported for human diploid fibroblasts. Mutation induction was investigated at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in normal and immortalized HMEC. Induced mutations at the HPRT locus as determined by 6-thioguanine resistance in normal primary HMEC were not observed following UV radiation. Mutation induction was observed at this locus UV-exposed immortalized HMEC. (author)

  16. DNA mismatch repair protein MSH2 dictates cellular survival in response to low dose radiation in endometrial carcinoma cells.

    LENUS (Irish Health Repository)

    Martin, Lynn M

    2013-07-10

    DNA repair and G2-phase cell cycle checkpoint responses are involved in the manifestation of hyper-radiosensitivity (HRS). The low-dose radioresponse of MSH2 isogenic endometrial carcinoma cell lines was examined. Defects in cell cycle checkpoint activation and the DNA damage response in irradiated cells (0.2 Gy) were evaluated. HRS was expressed solely in MSH2+ cells and was associated with efficient activation of the early G2-phase cell cycle checkpoint. Maintenance of the arrest was associated with persistent MRE11, γH2AX, RAD51 foci at 2 h after irradiation. Persistent MRE11 and RAD51 foci were also evident 24 h after 0.2 Gy. MSH2 significantly enhances cell radiosensitivity to low dose IR.

  17. Single nucleotide polymorphisms of DNA mismatch repair genes MSH2 and MLH1 confer susceptibility to esophageal cancer.

    Science.gov (United States)

    Sun, Ming-Zhong; Ju, Hui-Xiang; Zhou, Zhong-Wei; Jin, Hao; Zhu, Rong

    2014-01-01

    Defects in DNA mismatch repair genes like MSH2 and MLH1 confer increased risk of cancers. Here, single nucleotide polymorphisms (SNPs) in MSH2 and MLH1 were investigated for their potential contribution to the risk of esophageal cancer. This study recruited 614 participants from Affiliated Yancheng Hospital, School of Medicine, Southeast University, of which 289 were patients with esophageal cancer, and the remainder was healthy individuals who served as a control group. Two SNPs, MSH2 c.2063T>G and MLH1 IVS14-19A>G, were genotyped using PCR-RFLP. Statistical analysis was performed using chi-square test and logistic regression analysis. Carriers of the MSH2 c.2063G allele were at significantly higher risk for esophageal cancer compared to individuals with the TT genotype [OR = 3.36, 95% confidence interval (CI): 1.18-11.03]. The MLH1 IVS14-19A>G allele also conferred significantly increased (1.70-fold) for esophageal cancer compared to the AA genotype (OR = 1.70, 95% CI: 1.13-5.06). Further, the variant alleles interacted such that individuals with the susceptible genotypes at both MSH2 and MLH1 had a significantly exacerbated risk for esophageal cancer (OR = 12.38, 95% CI: 3.09-63.11). In brief, SNPs in the DNA mismatch repair genes MSH2 and MLH1 increase the risk of esophageal cancer. Molecular investigations are needed to uncover the mechanism behind their interaction effect.

  18. Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

    Energy Technology Data Exchange (ETDEWEB)

    Zavodna, Katarina; Krivulcik, Tomas; Bujalkova, Maria Gerykova [Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia); Slamka, Tomas; Martinicky, David; Ilencikova, Denisa [National Cancer Institute, Department of Oncologic Genetics, Klenova 1, 833 01 Bratislava (Slovakia); Bartosova, Zdena [Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia)

    2009-11-20

    Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or

  19. Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

    Directory of Open Access Journals (Sweden)

    Ilencikova Denisa

    2009-11-01

    Full Text Available Abstract Background Depending on the population studied, large genomic rearrangements (LGRs of the mismatch repair (MMR genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC. It has been reported that loss of heterozygosity (LOH at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. Methods The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. Results We found six rearrangements in the MSH2 gene (five deletions and dup5-6, and one aberration in the MLH1 gene (del5-6. The MSH2 deletions were of three types (del1, del1-3, del1-7. We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. Conclusion LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1

  20. Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

    International Nuclear Information System (INIS)

    Zavodna, Katarina; Krivulcik, Tomas; Bujalkova, Maria Gerykova; Slamka, Tomas; Martinicky, David; Ilencikova, Denisa; Bartosova, Zdena

    2009-01-01

    Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or

  1. Functional examination of MLH1, MSH2, and MSH6 intronic mutations identified in Danish colorectal cancer patients

    DEFF Research Database (Denmark)

    Petersen, Sanne M; Dandanell, Mette; Rasmussen, Lene J

    2013-01-01

    Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomi...

  2. First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome.

    Science.gov (United States)

    Ziada-Bouchaar, H; Sifi, K; Filali, T; Hammada, T; Satta, D; Abadi, N

    2017-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand-dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families.

  3. Nuclear translocation of mismatch repair proteins MSH2 and MSH6 as a response of cells to alkylating agents.

    Science.gov (United States)

    Christmann, M; Kaina, B

    2000-11-17

    Mammalian mismatch repair has been implicated in mismatch correction, the prevention of mutagenesis and cancer, and the induction of genotoxicity and apoptosis. Here, we show that treatment of cells specifically with agents inducing O(6)-methylguanine in DNA, such as N-methyl-N'-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea, elevates the level of MSH2 and MSH6 and increases GT mismatch binding activity in the nucleus. This inducible response occurs immediately after alkylation, is long-lasting and dose-dependent, and results from translocation of the preformed MutSalpha complex (composed of MSH2 and MSH6) from the cytoplasm into the nucleus. It is not caused by an increase in MSH2 gene activity. Cells expressing the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT), thus having the ability to repair O(6)-methylguanine, showed no translocation of MutSalpha, whereas inhibition of MGMT by O(6)-benzylguanine provoked the translocation. The results demonstrate that O(6)-methylguanine lesions are involved in triggering nuclear accumulation of MSH2 and MSH6. The finding that treatment of cells with O(6)-methylguanine-generating mutagens results in an increase of MutSalpha and GT binding activity in the nucleus indicates a novel type of genotoxic stress response.

  4. Identification of Factors Interacting with hMSH2 and hMLH1 in the Fetal Liver and Investigations of how Mitochondrial Dysfunction Creates a Mutator Phenotype

    DEFF Research Database (Denmark)

    Rasmussen, Anne Karin

    mutations. Mutations in MMR genes cause hereditary non-polyposis colon cancer. In an effort to identify unidentified genes involved in MMR and tissue-specific MMRassociated factors, we employed the yeast two-hybrid system, using the human hMSH2 as bait and a human fetal liver cDNA library as prey. We...... between mitochondrial activity and genomic instability. Mitochondrial dysfunction and genetic instability are characteristic features of cancer cells. Furthermore, mitochondrial dysfunction is a key feature of aging due to accumulation of mutations in mtDNA. Our studies in a yeast model system suggest......Increased spontaneous mutation frequency is associated with increased cancer risk. However, the relative contribution of spontaneous endogenous mutagenesis to carcinogenesis is not known today. Defects in the postreplication DNA mismatch repair (MMR) pathway are recognized to increase spontaneous...

  5. Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities

    Energy Technology Data Exchange (ETDEWEB)

    Edelbrock, Michael A., E-mail: Edelbrock@findlay.edu [The University of Findlay, 1000 North Main Street, Findlay, OH 45840 (United States); Kaliyaperumal, Saravanan, E-mail: Saravanan.Kaliyaperumal@hms.harvard.edu [Division of Comparative Medicine and Pathology, New England Primate Research Center, One Pine Hill Drive, Southborough, MA 01772 (United States); Williams, Kandace J., E-mail: Kandace.williams@utoledo.edu [University of Toledo College of Medicine and Life Sciences, Department of Biochemistry and Cancer Biology, 3000 Transverse Dr., Toledo, OH 43614 (United States)

    2013-03-15

    The field of DNA mismatch repair (MMR) has rapidly expanded after the discovery of the MutHLS repair system in bacteria. By the mid 1990s yeast and human homologues to bacterial MutL and MutS had been identified and their contribution to hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome) was under intense investigation. The human MutS homologue 6 protein (hMSH6), was first reported in 1995 as a G:T binding partner (GTBP) of hMSH2, forming the hMutSα mismatch-binding complex. Signal transduction from each DNA-bound hMutSα complex is accomplished by the hMutLα heterodimer (hMLH1 and hPMS2). Molecular mechanisms and cellular regulation of individual MMR proteins are now areas of intensive research. This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα, and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell. MSH6 is unstable in the absence of MSH2, however it is the DNA lesion-binding partner of this heterodimer. MSH6, but not MSH2, has a conserved Phe-X-Glu motif that recognizes and binds several different DNA structural distortions, initiating different cellular responses. hMSH6 also contains the nuclear localization sequences required to shuttle hMutSα into the nucleus. For example, upon binding to O{sup 6}meG:T, MSH6 triggers a DNA damage response that involves altered phosphorylation within the N-terminal disordered domain of this unique protein. While many investigations have focused on MMR as a post-replication DNA repair mechanism, MMR proteins are expressed and active in all phases of the cell cycle. There is much more to be discovered about regulatory cellular roles that require the presence of MutSα and, in particular, MSH6.

  6. Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities

    International Nuclear Information System (INIS)

    Edelbrock, Michael A.; Kaliyaperumal, Saravanan; Williams, Kandace J.

    2013-01-01

    The field of DNA mismatch repair (MMR) has rapidly expanded after the discovery of the MutHLS repair system in bacteria. By the mid 1990s yeast and human homologues to bacterial MutL and MutS had been identified and their contribution to hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome) was under intense investigation. The human MutS homologue 6 protein (hMSH6), was first reported in 1995 as a G:T binding partner (GTBP) of hMSH2, forming the hMutSα mismatch-binding complex. Signal transduction from each DNA-bound hMutSα complex is accomplished by the hMutLα heterodimer (hMLH1 and hPMS2). Molecular mechanisms and cellular regulation of individual MMR proteins are now areas of intensive research. This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα, and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell. MSH6 is unstable in the absence of MSH2, however it is the DNA lesion-binding partner of this heterodimer. MSH6, but not MSH2, has a conserved Phe-X-Glu motif that recognizes and binds several different DNA structural distortions, initiating different cellular responses. hMSH6 also contains the nuclear localization sequences required to shuttle hMutSα into the nucleus. For example, upon binding to O 6 meG:T, MSH6 triggers a DNA damage response that involves altered phosphorylation within the N-terminal disordered domain of this unique protein. While many investigations have focused on MMR as a post-replication DNA repair mechanism, MMR proteins are expressed and active in all phases of the cell cycle. There is much more to be discovered about regulatory cellular roles that require the presence of MutSα and, in particular, MSH6

  7. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management

    Directory of Open Access Journals (Sweden)

    Ramsoekh Dewkoemar

    2009-12-01

    Full Text Available Abstract Background Lynch syndrome (LS is associated with a high risk for colorectal cancer (CRC and extracolonic malignancies, such as endometrial carcinoma (EC. The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers. Methods The studypopulation consisted out of 67 proven LS families. Clinical information including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and compared using Kaplan Meier survival analysis. Results MSH6 mutation carriers, both males and females had the lowest risk for developing CRC at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males. With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age 70 years (61% compared to MLH1 (25% and MSH2 (49%. Also, the age of EC onset was delayed by 5-10 years in comparison with MLH1 and MSH2. Conclusions Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2 and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers compared to MLH1 and MSH2 mutation carriers.

  8. Regulated expression of genes inserted at the human chromosomal β-globin locus by homologous recombination

    International Nuclear Information System (INIS)

    Nandi, A.K.; Roginski, R.S.; Gregg, R.G.; Smithies, O.; Skoultchi, A.I.

    1988-01-01

    The authors have examined the effect of the site of integration on the expression of cloned genes introduced into cultured erythroid cells. Smithies et al. reported the targeted integration of DNA into the human β-globin locus on chromosome 11 in a mouse erythroleukemia-human cell hybrid. These hybrid cells can undergo erythroid differentiation leading to greatly increased mouse and human β-globin synthesis. By transfection of these hybrid cells with a plasmid carrying a modified human β-globin gene and a foreign gene composed of the coding sequence of the bacterial neomycin-resistance gene linked to simian virus 40 transcription signals (SVneo), cells were obtained in which the two genes are integrated at the β-globin locus on human chromosome 11 or at random sites. When they examined the response of the integrated genes to cell differentation, they found that the genes inserted at the β-globin locus were induced during differentiation, whereas randomly positioned copies were not induced. Even the foreign SVneo gene was inducible when it had been integrated at the β-globin locus. The results show that genes introduced at the β-globin locus acquire some of the regulatory properties of globin genes during erythroid differentiation

  9. An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents.

    Science.gov (United States)

    Worrillow, Lisa J; Travis, Lois B; Smith, Alexandra G; Rollinson, Sara; Smith, Andrew J; Wild, Christopher P; Holowaty, Eric J; Kohler, Betsy A; Wiklund, Tom; Pukkala, Eero; Roman, Eve; Morgan, Gareth J; Allan, James M

    2003-08-01

    We sought to determine whether the -6 exon 13 T>C polymorphism in the DNA mismatch repair gene hMSH2 modulates susceptibility to acute myeloid leukemia after therapy and particularly after O(6)-guanine alkylating chemotherapy. We also determined the extent of microsatellite instability (MSI) in therapy-related acute myeloid leukemia (t-AML) as a marker of dysfunctional DNA mismatch repair. Using a novel restriction fragment length polymorphism, verified by direct sequencing, we have genotyped 91 t-AML cases, 420 de novo acute myeloid leukemia cases, and 837 controls for the hMSH2 -6 exon 13 polymorphism. MSI was evaluated in presentation bone marrow from 34 cases using the mononucleotide microsatellite markers BAT16, BAT25, and BAT26. Distribution of the hMSH2 -6 exon 13 polymorphism was not significantly different between de novo acute myeloid leukemia cases and controls, with heterozygotes and homozygotes for the variant (C) allele representing 12.2 and 1.6%, respectively, of the control population. However, the variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O(6)-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (odds ratio, 4.02; 95% confidence interval, 1.40-11.37). Thirteen of 34 (38%) t-AML cases were MSI positive, and 2 of these 13 cases were homozygous for the variant (C) allele, a frequency substantially higher than in the control population. Association of the hMSH2 -6 exon 13 variant (C) allele with leukemia after O(6)-guanine alkylating agents implicates this allele in conferring a nondisabling DNA mismatch repair defect with concomitant moderate alkylation tolerance, which predisposes to the development of t-AML via the induction of DNA mismatch repair-disabling mutations and high-grade MSI. Homozygosity for the hMSH2 variant in 2 of 13 MSI-positive t-AML cases provides some support for this model.

  10. Arabidopsis thaliana population analysis reveals high plasticity of the genomic region spanning MSH2, AT3G18530 and AT3G18535 genes and provides evidence for NAHR-driven recurrent CNV events occurring in this location.

    Science.gov (United States)

    Zmienko, Agnieszka; Samelak-Czajka, Anna; Kozlowski, Piotr; Szymanska, Maja; Figlerowicz, Marek

    2016-11-08

    Intraspecies copy number variations (CNVs), defined as unbalanced structural variations of specific genomic loci, ≥1 kb in size, are present in the genomes of animals and plants. A growing number of examples indicate that CNVs may have functional significance and contribute to phenotypic diversity. In the model plant Arabidopsis thaliana at least several hundred protein-coding genes might display CNV; however, locus-specific genotyping studies in this plant have not been conducted. We analyzed the natural CNVs in the region overlapping MSH2 gene that encodes the DNA mismatch repair protein, and AT3G18530 and AT3G18535 genes that encode poorly characterized proteins. By applying multiplex ligation-dependent probe amplification and droplet digital PCR we genotyped those genes in 189 A. thaliana accessions. We found that AT3G18530 and AT3G18535 were duplicated (2-14 times) in 20 and deleted in 101 accessions. MSH2 was duplicated in 12 accessions (up to 12-14 copies) but never deleted. In all but one case, the MSH2 duplications were associated with those of AT3G18530 and AT3G18535. Considering the structure of the CNVs, we distinguished 5 genotypes for this region, determined their frequency and geographical distribution. We defined the CNV breakpoints in 35 accessions with AT3G18530 and AT3G18535 deletions and tandem duplications and showed that they were reciprocal events, resulting from non-allelic homologous recombination between 99 %-identical sequences flanking these genes. The widespread geographical distribution of the deletions supported by the SNP and linkage disequilibrium analyses of the genomic sequence confirmed the recurrent nature of this CNV. We characterized in detail for the first time the complex multiallelic CNV in Arabidopsis genome. The region encoding MSH2, AT3G18530 and AT3G18535 genes shows enormous variation of copy numbers among natural ecotypes, being a remarkable example of high Arabidopsis genome plasticity. We provided the molecular

  11. Physical map and one-megabase sequencing of the human immunoglobulin lambda locus

    Directory of Open Access Journals (Sweden)

    Geraldo A.S. Passos Jr.

    1998-06-01

    Full Text Available The human immunoglobulin lambda (IGL locus is located on chromosome 22q11.1-q11.2 and contains the genes responsible for the immunoglobulin lambda light chains. This locus was recently mapped (physical map and its 1-Mb DNA totally sequenced. In this review we focus on the characterization of the v-lambda genes, its chromosomal location, genomics and sequencing of the IGL locus.O locus IGL humano está localizado no cromosomo 22q11.1-q11.2 e contém os genes responsáveis pelas cadeias leves de imunoglobulina tipo lambda. Este locus foi recentemente mapeado (mapa físico e seu 1 Mb DNA totalmente sequenciado. Nesta revisão focamos os principais resultados de caracterização dos genes v-lambda, sua localização cromossômica, a genômica e seqüenciamento do locus IGL.

  12. Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancer

    International Nuclear Information System (INIS)

    Vodusek, Ana Lina; Novakovic, Srdjan; Stegel, Vida; Jereb, Berta

    2011-01-01

    Some tumour suppressor genes (BRCA2) and mismatch repair genes (MSH2, MLH1) are correlated with an increased risk for male breast cancer. Our patient developed secondary breast cancer after the treatment for Hodgkin’s disease in childhood. DNA was isolated from the patients’ blood and screened for mutations, polymorphisms and variants in BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes. We found no mutations but common polymorphisms, and three variants in mismatch repair genes. Nucleotide variants c.2006-6T>C and p.G322D in MSH2 might be correlated with male breast cancer

  13. BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations.

    Science.gov (United States)

    Deihimi, Safoora; Lev, Avital; Slifker, Michael; Shagisultanova, Elena; Xu, Qifang; Jung, Kyungsuk; Vijayvergia, Namrata; Ross, Eric A; Xiu, Joanne; Swensen, Jeffrey; Gatalica, Zoran; Andrake, Mark; Dunbrack, Roland L; El-Deiry, Wafik S

    2017-06-20

    Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

  14. Age-Dependent Cancer Risk Is not Different in between MSH2 and MLH1 Mutation Carriers

    International Nuclear Information System (INIS)

    Olschwang, S.; Olschwang, S.; Yu, K.

    2009-01-01

    Lynch syndrome is mostly characterized by early-onset colorectal and endometrial adenocarcinomas. Over 90% of the causal mutations occur in two mismatch repair genes, MSH2 and MLH1. The aim of this study was to evaluate the age-dependent cancer risk in MSH2 or MLH1 mutation carriers from data of DNA diagnostic laboratories. To avoid overestimation, evaluation was based on the age-dependent proportion of mutation carriers in asymptomatic first-degree relatives of identified mutation carriers. Data from 859 such eligible relatives were collected from 8 centers; 387 were found to have inherited the mutation from their relatives. Age-dependent risks were calculated either using a nonparametric approach for four discrete age groups or assuming a modified Weibull distribution for the dependence of risk on age. Cancer risk was estimated starting at 28 (25-32 0.68 confidence interval) and to reach near 0.70 at 70 years. The risks were very similar for MSH2 and MLH1 mutation carriers. Although not statistically significant, the risk in males appeared to precede that for females by ten years. This difference needs to be investigated on a larger dataset. If confirmed, this would indicate that the onset of the colonoscopic surveillance may be different in male and female mutation carriers.

  15. Association of a novel point mutation in MSH2 gene with familial multiple primary cancers

    Directory of Open Access Journals (Sweden)

    Hai Hu

    2017-10-01

    Full Text Available Abstract Background Multiple primary cancers (MPC have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues. Methods We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC. Results We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients. Conclusion Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome.

  16. Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome

    Energy Technology Data Exchange (ETDEWEB)

    Lidsky, A.S.; Law, M.L.; Morse, H.G.; Kao, F.T.; Rabin, M.; Ruddle, F.H.; Woo, S.L.C.

    1985-09-01

    Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase. To define the regional map position of the disease locus and the PAH gene on human chromosome 12, DNA was isolated from human-hamster somatic cell hybrids with various deletions of human chromosome 12 and was analyzed by Southern blot analysis using the human cDNA PAH clone as a hybridization probe. From these results, together with detailed biochemical and cytogenetic characterization of the hybrid cells, the region on chromosome 12 containing the human PAH gene has been defined as 12q14.3..-->..qter. The PAH map position on chromosome 12 was further localized by in situ hybridization of /sup 125/I-labeled human PAH cDNA to chromosomes prepared from a human lymphoblastoid cell line. Results of these experiments demonstrated that the region on chromosome 12 containing the PAH gene and the PKU locus in man is 12q22..-->..12q24.1. These results not only provide a regionalized map position for a major human disease locus but also can serve as a reference point for linkage analysis with other DNA markers on human chromosome 12.

  17. Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome

    International Nuclear Information System (INIS)

    Lidsky, A.S.; Law, M.L.; Morse, H.G.; Kao, F.T.; Rabin, M.; Ruddle, F.H.; Woo, S.L.C.

    1985-01-01

    Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase. To define the regional map position of the disease locus and the PAH gene on human chromosome 12, DNA was isolated from human-hamster somatic cell hybrids with various deletions of human chromosome 12 and was analyzed by Southern blot analysis using the human cDNA PAH clone as a hybridization probe. From these results, together with detailed biochemical and cytogenetic characterization of the hybrid cells, the region on chromosome 12 containing the human PAH gene has been defined as 12q14.3→qter. The PAH map position on chromosome 12 was further localized by in situ hybridization of 125 I-labeled human PAH cDNA to chromosomes prepared from a human lymphoblastoid cell line. Results of these experiments demonstrated that the region on chromosome 12 containing the PAH gene and the PKU locus in man is 12q22→12q24.1. These results not only provide a regionalized map position for a major human disease locus but also can serve as a reference point for linkage analysis with other DNA markers on human chromosome 12

  18. Human γ-globin genes silenced independently of other genes in the β-globin locus.

    NARCIS (Netherlands)

    N.O. Dillon (Niall); F.G. Grosveld (Frank)

    1991-01-01

    textabstractErythropoiesis during human development is characterized by switches in expression of beta-like globin genes during the transition from the embryonic through fetal to adult stages. Activation and high-level expression of the genes is directed by the locus control region (LCR), located 5'

  19. A Dual Reporter Mouse Model of the Human β-Globin Locus: Applications and Limitations

    NARCIS (Netherlands)

    P. Papadopoulos (Petros); L. Gutiérrez (Laura); R. van der Linden (Reinier); J. Kong-a-San (John); A. Maas (Alex); D.D. Drabek (Dubravka); G.P. Patrinos (George); J.N.J. Philipsen (Sjaak); F.G. Grosveld (Frank)

    2012-01-01

    textabstractThe human β-globin locus contains the β-like globin genes (i.e. fetal γ-globin and adult β-globin), which heterotetramerize with α-globin subunits to form fetal or adult hemoglobin. Thalassemia is one of the commonest inherited disorders in the world, which results in quantitative

  20. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

    Science.gov (United States)

    Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

  1. Updated listing of haplotypes at the human phenylalanine hydroxylase (PAH) locus

    Energy Technology Data Exchange (ETDEWEB)

    Eisensmith, R.C.; Woo, S.L.C. (Baylor College of Medicine, Houston, TX (United States))

    1992-12-01

    Analysis of mutant PAH chromosomes has identified approximately 60 different single-base substitutions and deletions within the PAH locus. Nearly all of these molecular lesions are in strong linkage disequilibrium with specific RFLP haplotypes in different ethnic populations. Thus, haplotype analysis is not only useful for diagnostic purposes but is proving to be a valuable tool in population genetic studies of the origin and spread of phenylketonuria alleles in human populations. PCR-based methods have been developed to detect six of the eight polymorphic restriction sites used for determination of RFLP haplotypes at the PAH locus. A table of the proposed expanded haplotypes is given.

  2. Human amyloid beta protein gene locus: HaeIII RFLP

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, J E; Gonzalez-DeWhitt, P A; Fuller, F; Cordell, B; Frossard, P M [California Biotechnology Inc., Mountain View (USA); Tinklenberg, J R; Davies, H D; Eng, L F; Yesavage, J A [Stanford Univ. School of Medicine, Palo Alto, CA (USA)

    1988-07-25

    A 2.2 kb EcoRI-EcoRI fragment from the 5{prime} end of the human amyloid beta protein cDNA was isolated from a human fibroblast cDNA library and subcloned into pGEM3. HaeIII (GGCC) detects 6 invariant bands at 0.5 kb, 1.0 kb, 1.1 kb, 1.3 kb, 1.4 kb and 1.6 kb and a two-allele polymorphism with bands at either 1.9 kb or 2.1 kb. Its frequency was studied in 50 North Americans. Human amyloid beta protein gene mapped to the long arm of chromosome 21 (21q11.2-21q21) by Southern blot analysis of human-rodent somatic cell hybrids. Co-dominant segregation was observed in two families (15 individuals).

  3. Human estrogen receptor (ESR) gene locus: PssI dimorphism

    Energy Technology Data Exchange (ETDEWEB)

    Coleman, R T; Taylor, J E; Frossard, P M [California Biotechnology Inc., Mountain View, CA (USA); Shine, J J [Garvan Institute, Darlinghurst (Australia)

    1988-07-25

    pESR-2, a 2.1 kb partial cDNA containing the entire translated sequence of the human estrogen receptor mRNA isolated from MCF-7 human breast cancer cells, was subcloned in the Eco RI site of pBR322. PssI (PuGGNCCPy) identifies a single two-allele polymorphism with bands at either 1.7 or 1.4 kb, as well as invariant bands at 12.6, 9.3, 4.1, 3.7, 2.4, 2.2, and 1.2 kb. Its frequency was studied in 77 unrelated North American Caucasians. The human estrogen receptor gene has been localized to 6q24 -- q27 by in situ hybridization. Co-dominant segregation is demonstrated in one family (8 individuals).

  4. Cadmium(Cd)-induced oxidative stress down-regulates the gene expression of DNA mismatch recognition proteins MutS homolog 2 (MSH2) and MSH6 in zebrafish (Danio rerio) embryos

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Todd, E-mail: toddhsu@mail.ntou.edu.tw [Institute of Bioscience and Biotechnology and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan (China); Huang, Kuan-Ming; Tsai, Huei-Ting; Sung, Shih-Tsung; Ho, Tsung-Nan [Institute of Bioscience and Biotechnology and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan (China)

    2013-01-15

    DNA mismatch repair (MMR) of simple base mismatches and small insertion-deletion loops in eukaryotes is initiated by the binding of the MutS homolog 2 (MSH2)-MSH6 heterodimer to mismatched DNA. Cadmium (Cd) is a genotoxic heavy metal that has been recognized as a human carcinogen. Oxidant stress and inhibition of DNA repair have been proposed as major factors underlying Cd genotoxicity. Our previous studies indicated the ability of Cd to disturb the gene expression of MSH6 in zebrafish (Danio rerio) embryos. This study was undertaken to explore if Cd-induced oxidative stress down-regulated MSH gene activities. Following the exposure of zebrafish embryos at 1 h post fertilization (hpf) to sublethal concentrations of Cd at 3-5 {mu}M for 4 or 9 h, a parallel down-regulation of MSH2, MSH6 and Cu/Zn superoxide dismutase (Cu/Zn-SOD) gene expression was detected by real-time RT-PCR and the expression levels were 40-50% of control after a 9-h exposure. Cd exposure also induced oxidative stress, yet no inhibition of catalase gene activity was observed. Whole mount in situ hybridization revealed a wide distribution of msh6 mRNA in the head regions of 10 hpf embryos and pretreatment of embryos with antioxidants butylhydroxytoluene (BHT), D-mannitol or N-acetylcysteine (NAC) at 1-10 {mu}M restored Cd-suppressed msh6 expression. QPCR confirmed the protective effects of antioxidants on Cd-suppressed msh2/msh6 mRNA production. Down-regulated MSH gene activities reaching about 50% of control were also induced in embryos exposed to paraquat, a reactive oxygen species (ROS)-generating herbicide, or hydrogen peroxide at 200 {mu}M. Hence, Cd at sublethal levels down-regulates msh2/msh6 expression primarily via ROS as signaling molecules. The transcriptional activation of human msh6 is known to be fully dependent on the specificity factor 1 (Sp1). Cd failed to inhibit the DNA binding activity of zebrafish Sp1 unless at lethal concentrations based on band shift assay, therefore

  5. A novel heterozygous germline deletion in MSH2 gene in a five generation Chinese family with Lynch syndrome

    OpenAIRE

    Wu, Bin; Ji, Wuyang; Liang, Shengran; Ling, Chao; You, Yan; Xu, Lai; Zhong, Min-Er; Xiao, Yi; Qiu, Hui-Zhong; Lu, Jun-Yang; Banerjee, Santasree

    2017-01-01

    Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6 and PMS2. Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five ge...

  6. Further RFLPs at the human tyrosine hydroxylase locus

    Energy Technology Data Exchange (ETDEWEB)

    Koerner, J; Uhlhaas, S; Propping, P; Gal, A [Institut fuer Humangenetik der Universitaet, Bonn (West Germany); Mallet, J [CNRS, Gif-sur-Yvette (France)

    1988-09-26

    The human cDNA clone (Ty7) of tyrosine hydroxylase was used. A two-allele (C1 and C2) Bg1II RFLP has been described recently with bands either at 6.9 or 8.4 kb (2). In addition, a faint invariant band appears at 9.0 kb. A third Bg1II allele (C3) with a band at 8.0 kb was detected. The allele frequency was studied in 35 and 39 unrelated Caucasians. Co-dominant inheritance for both RFLPs described here was demonstrated in 6 nuclear kindreds. RFLPs were observed under normal hybridization and wash stringencies.

  7. RFLP for TaqI at the human tyrosinase locus

    Energy Technology Data Exchange (ETDEWEB)

    Spritz, R; Strunk, K; Oetting, W; King, R

    1988-10-25

    A 1.4-kb EcoRI-PstI fragment from the mouse tyrosinase cDNA plasmid pTyrs-33 containing virtually the complete coding sequences. TaqI identifies a two-allele polymorphism with fragments of either 2.8 kb or 2.4 kb that contain most of the tyrosinase coding region. Three weak (1.4 kb, 0.9 kb, and 0.6 kb) and two very weak (5.0 and 3.2 kb) constant bands are also seen. The human tyrosinase gene has been regionally mapped to 11q14->21, and a wealy cross-hybridizing tyrosinase-related sequence mapped to 11p11.2->cen. Co-dominant segregation has been shown in two families. The RFLP was observed under normal hybridization and wash conditions.

  8. Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung

    Directory of Open Access Journals (Sweden)

    A. Gomes

    2014-01-01

    Full Text Available Five years survival of lung cancer is 16%, significantly lower than in prostate (99.9%, breast (88.5% and colon (64.1% carcinomas. When diagnosed in the surgical stage it increases to 50% but this group only comprises 14–16% of the cases. DNA methylation has emerged as a potential cancer-specific biomarker. Hypermethylation of CpG islands located in the promoter regions of tumour suppressor genes is now firmly established as an important mechanism for gene inactivation.This retrospective study included 40 squamous cell carcinomas and 40 adenocarcinomas in various surgical TNM stages to define methylation profile and possible silencing of DNA repair genes – MLH1 and MSH2 – using Methylation-Specific PCR and protein expression by immunohistochemistry in tumoural tissue, preneoplastic lesions and respiratory epithelium with normal histological features.The protein expression of MLH1 and MSH2 genes, in the available preneoplastic lesions and in normal cylindrical respiratory epithelium appeared reduced. The frequency of promoter hypermethylation found on these DNA repair genes was elevated, with a higher prevalence of methylation of MLH1 gene in 72% of squamous cell carcinoma. The differences are not so obvious for MSH2 promoter hypermethylation. No correlation was found among the status of methylation, the protein expression and the clinicopathological characteristics.With a larger study, a better characterization of the hypermethylation status of neoplastic and preneoplastic lesions in small biopsies would be achieved, inherent to tumour histology, heterogeneity and preservation, and finally differences in the study population to elucidate other possible mechanisms of altered expression of the hMLH1 and hMSH. Resumo: A sobrevivência aos cinco anos no cancro do pulmão é de 16%, significativamente inferior que nos carcinomas na próstata (99,9%, mama (88,5% e cólon (64,1%. Quando diagnosticado na fase cir

  9. Association between promoter methylation of MLH1 and MSH2 and reactive oxygen species in oligozoospermic men-A pilot study.

    Science.gov (United States)

    Gunes, S; Agarwal, A; Henkel, R; Mahmutoglu, A M; Sharma, R; Esteves, S C; Aljowair, A; Emirzeoglu, D; Alkhani, A; Pelegrini, L; Joumah, A; Sabanegh, E

    2018-04-01

    MLH1 and MSH2 are important genes for DNA mismatch repair and crossing over during meiosis and are implicated in male infertility. Therefore, the methylation patterns of the DNA mismatch repair genes MLH1 and MSH2 in oligozoospermic males were investigated. Ten oligozoospermic patients and 29 normozoospermic donors were analysed. Methylation profiles of the MLH1 and MSH2 promotors were analysed. In addition, sperm motility and seminal reactive oxygen species (ROS) were recorded. Receiver operating characteristic (ROC) analysis was conducted to determine the accuracy of the DNA methylation status of MLH1 and MSH2 to distinguish between oligozoospermic and normozoospermic men. In oligozoospermic men, MLH1 was significantly (p = .0013) more methylated compared to normozoospermic men. Additionally, there was a significant positive association (r = .384; p = .0159) between seminal ROS levels and MLH1 methylation. Contrary, no association between MSH2 methylation and oligozoospermia was found. ROC curve analysis for methylation status of MLH1 was significant (p = .0275) with an area under the curve of 61.1%, a sensitivity of 22.2% and a specificity of 100.0%. This pilot study indicates oligozoospermic patients have more methylation of MLH1 than normozoospermic patients. Whether hypermethylation of the MLH1 promoter plays a role in repairing relevant mismatches of sperm DNA strands in idiopathic oligozoospermia warrants further investigation. © 2017 Blackwell Verlag GmbH.

  10. A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance-functional analysis reveals the pathogenic one

    DEFF Research Database (Denmark)

    Kantelinen, Jukka; Hansen, Thomas V O; Kansikas, Minttu

    2011-01-01

    Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS...... and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence...... identified VUS before predictive gene testing and genetic counseling are offered to a family....

  11. A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants

    DEFF Research Database (Denmark)

    Drost, Mark; Zonneveld, José B M; van Hees, Sandrine

    2012-01-01

    amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH......2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development...... of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS....

  12. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

    Directory of Open Access Journals (Sweden)

    Marina Kovalenko

    Full Text Available The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111 with mice carrying a conditional (floxed Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

  13. Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

    Science.gov (United States)

    Cariola, Filomena; Disciglio, Vittoria; Valentini, Anna M; Lotesoriere, Claudio; Fasano, Candida; Forte, Giovanna; Russo, Luciana; Di Carlo, Antonio; Guglielmi, Floranna; Manghisi, Andrea; Lolli, Ivan; Caruso, Maria L; Simone, Cristiano

    2018-04-01

    Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

  14. Murine and human b locus pigmentation genes encode a glycoprotein (gp75) with catalase activity

    International Nuclear Information System (INIS)

    Halaban, R.; Moellmann, G.

    1990-01-01

    Melanogenesis is regulated in large part by tyrosinase, and defective tyrosinase leads to albinism. The mechanisms for other pigmentation determinants (e.g., those operative in tyrosinase-positive albinism and in murine coat-color mutants) are not yet known. One murine pigmentation gene, the brown (b) locus, when mutated leads to a brown (b/b) or hypopigmentated (B lt /B lt ) coat versus the wild-type black (B/B). The authors show that the b locus codes for a glycoprotein with the activity of a catalase (catalase B). Only the c locus protein is a tyrosinase. Because peroxides may be by-products of melanogenic activity and hydrogen peroxide in particular is known to destroy melanin precursors and melanin, they conclude that pigmentation is controlled not only by tyrosinase but also by a hydroperoxidase. The studies indicate that catalase B is identical with gp75, a known human melanosomal glycoprotein; that the b mutation is in a heme-associated domain; and that the B lt mutation renders the protein susceptible to rapid proteolytic degradation

  15. Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs.

    Science.gov (United States)

    Hinrichsen, Inga; Kemp, Matthias; Peveling-Oberhag, Jan; Passmann, Sandra; Plotz, Guido; Zeuzem, Stefan; Brieger, Angela

    2014-01-01

    Epigenetic silencing of tumour suppressor genes has been observed in various cancers. Looking at hepatocellular carcinoma (HCC) specific protein silencing was previously demonstrated to be associated with the Hepatitis C virus (HCV). However, the proposed HCV dependent promoter methylation of DNA mismatch repair (MMR) genes and thereby enhanced progression of hepatocarcinogenesis has been the subject of controversial discussion. We investigated promoter methylation pattern of the MMR genes MLH1, MSH2 and PMS2 as well as the cyclin-dependent kinase inhibitor 2A gene (p16) in 61 well characterized patients with HCCs associated with HCV, Hepatitis B virus infection or alcoholic liver disease. DNA was isolated from formalin-fixed, paraffin-embedded tumour and non-tumour adjacent tissue and analysed by methylation-specific PCR. Moreover, microsatellite analysis was performed in tissues showing methylation in MMR gene promoters. Our data demonstrated that promoter methylation of MLH1, MSH2, PMS2 and p16 is present among all considered HCCs. Hereby, promoter silencing was detectable more frequently in advanced-stage HCCs than in low-stage ones. However, there was no significant correlation between aberrant DNA methylation of MMR genes or p16 and HCV infection in related HCC specimens. In summary, we show that promoter methylation of essential MMR genes and p16 is detectable in HCCs most dominantly in pT3 stage tumour cases. Since loss of MMR proteins was previously described to be not only responsible for tumour development but also for chemotherapy resistance, the knowledge of mechanisms jointly responsible for HCC progression might enable significant improvement of individual HCC therapy in the future.

  16. Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs.

    Directory of Open Access Journals (Sweden)

    Inga Hinrichsen

    Full Text Available Epigenetic silencing of tumour suppressor genes has been observed in various cancers. Looking at hepatocellular carcinoma (HCC specific protein silencing was previously demonstrated to be associated with the Hepatitis C virus (HCV. However, the proposed HCV dependent promoter methylation of DNA mismatch repair (MMR genes and thereby enhanced progression of hepatocarcinogenesis has been the subject of controversial discussion. We investigated promoter methylation pattern of the MMR genes MLH1, MSH2 and PMS2 as well as the cyclin-dependent kinase inhibitor 2A gene (p16 in 61 well characterized patients with HCCs associated with HCV, Hepatitis B virus infection or alcoholic liver disease. DNA was isolated from formalin-fixed, paraffin-embedded tumour and non-tumour adjacent tissue and analysed by methylation-specific PCR. Moreover, microsatellite analysis was performed in tissues showing methylation in MMR gene promoters. Our data demonstrated that promoter methylation of MLH1, MSH2, PMS2 and p16 is present among all considered HCCs. Hereby, promoter silencing was detectable more frequently in advanced-stage HCCs than in low-stage ones. However, there was no significant correlation between aberrant DNA methylation of MMR genes or p16 and HCV infection in related HCC specimens. In summary, we show that promoter methylation of essential MMR genes and p16 is detectable in HCCs most dominantly in pT3 stage tumour cases. Since loss of MMR proteins was previously described to be not only responsible for tumour development but also for chemotherapy resistance, the knowledge of mechanisms jointly responsible for HCC progression might enable significant improvement of individual HCC therapy in the future.

  17. Asynchronous DNA replication within the human β-globin gene locus

    International Nuclear Information System (INIS)

    Epner, E.; Forrester, W.C.; Groudine, M.

    1988-01-01

    The timing of DNA replication of the human β-globin gene locus has been studied by blot hybridization of newly synthesized BrdUrd-substituted DNA from cells in different stages of the S phase. Using probes that span >120 kilobases across the human β-globin gene locus, the authors show that the majority of this domain replicates in early S phase in the human erythroleukemia cell line K562 and in middle-to-late S phase in the lymphoid cell line Manca. However, in K562 cells three small regions display a strikingly different replication pattern than adjacent sequences. These islands, located in the inter-γ-globin gene region and approximately 20 kilobases 5' to the ε-globin gene and 20 kilobases 3' to the β-globin gene, replicate later and throughout S phase. A similar area is also present in the α-globin gene region in K562 cells. They suggest that these regions may represent sites of termination of replication forks

  18. Nonviral Gene Targeting at rDNA Locus of Human Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Youjin Hu

    2013-01-01

    Full Text Available Background. Genetic modification, such as the addition of exogenous genes to the MSC genome, is crucial to their use as cellular vehicles. Due to the risks associated with viral vectors such as insertional mutagenesis, the safer nonviral vectors have drawn a great deal of attention. Methods. VEGF, bFGF, vitamin C, and insulin-transferrin-selenium-X were supplemented in the MSC culture medium. The cells’ proliferation and survival capacity was measured by MTT, determination of the cumulative number of cells, and a colony-forming efficiency assay. The plasmid pHr2-NL was constructed and nucleofected into MSCs. The recombinants were selected using G418 and characterized using PCR and Southern blotting. Results. BFGF is critical to MSC growth and it acted synergistically with vitamin C, VEGF, and ITS-X, causing the cells to expand significantly. The neomycin gene was targeted to the rDNA locus of human MSCs using a nonviral human ribosomal targeting vector. The recombinant MSCs retained multipotential differentiation capacity, typical levels of hMSC surface marker expression, and a normal karyotype, and none were tumorigenic in nude mice. Conclusions. Exogenous genes can be targeted to the rDNA locus of human MSCs while maintaining the characteristics of MSCs. This is the first nonviral gene targeting of hMSCs.

  19. Uptake of inorganic mercury by human locus ceruleus and corticomotor neurons: implications for amyotrophic lateral sclerosis

    Science.gov (United States)

    2013-01-01

    Background Environmental toxins are suspected to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In an attempt to determine which pathways these toxins can use to enter motor neurons we compared the distribution of mercury in the CNS of a human and of mice that had been exposed to inorganic mercury. Results In the human who had been exposed to metallic mercury, mercury was seen predominantly in the locus ceruleus and corticomotor neurons, as well as in scattered glial cells. In mice that had been exposed to mercury vapor or mercuric chloride, mercury was present in lower motor neurons in the spinal cord and brain stem. Conclusions In humans, inorganic mercury can be taken up predominantly by corticomotor neurons, possibly when the locus ceruleus is upregulated by stress. This toxin uptake into corticomotor neurons is in accord with the hypothesis that ALS originates in these upper motor neurons. In mice, inorganic mercury is taken up predominantly by lower motor neurons. The routes toxins use to enter motor neurons depends on the nature of the toxin, the duration of exposure, and possibly the amount of stress (for upper motor neuron uptake) and exercise (for lower motor neuron uptake) at the time of toxin exposure. PMID:24252585

  20. Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH)

    DEFF Research Database (Denmark)

    Staaf, Johan; Törngren, Therese; Rambech, Eva

    2008-01-01

    deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged...

  1. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers : A study of hereditary nonpolyposis colorectal cancer families

    NARCIS (Netherlands)

    Vasen, HFA; Stormorken, A; Menko, FH; Nagengast, FM; Kleibeuker, JH; Griffioen, G; Taal, BG; Moller, P; Wijnen, JT

    2001-01-01

    Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and

  2. Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States

    NARCIS (Netherlands)

    F. Kastrinos (Fay); E.M. Stoffel (Elena); J. Balmana (Judith); E.W. Steyerberg (Ewout); R. Mercado (Rowena); S. Syngal (Sapna)

    2008-01-01

    textabstractBackground and Aims: Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression. Methods: This is a

  3. A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance-functional analysis reveals the pathogenic one

    DEFF Research Database (Denmark)

    Kantelinen, Jukka; Hansen, Thomas V O; Kansikas, Minttu

    2011-01-01

    Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS...

  4. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families.

    NARCIS (Netherlands)

    Vasen, H.F.; Stormorken, A.; Menko, F.H.; Nagengast, F.M.; Kleibeuker, J.H.; Griffioen, G.; Taal, B.G.; Moller, P.; Wijnen, J.T.

    2001-01-01

    PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and

  5. Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

    Directory of Open Access Journals (Sweden)

    Stulp Rein P

    2008-02-01

    Full Text Available Abstract Lynch syndrome (HNPCC is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable, it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.

  6. Coordination of Rad1-Rad10 interactions with Msh2-Msh3, Saw1 and RPA is essential for functional 3' non-homologous tail removal.

    Science.gov (United States)

    Eichmiller, Robin; Medina-Rivera, Melisa; DeSanto, Rachel; Minca, Eugen; Kim, Christopher; Holland, Cory; Seol, Ja-Hwan; Schmit, Megan; Oramus, Diane; Smith, Jessica; Gallardo, Ignacio F; Finkelstein, Ilya J; Lee, Sang Eun; Surtees, Jennifer A

    2018-04-06

    Double strand DNA break repair (DSBR) comprises multiple pathways. A subset of DSBR pathways, including single strand annealing, involve intermediates with 3' non-homologous tails that must be removed to complete repair. In Saccharomyces cerevisiae, Rad1-Rad10 is the structure-specific endonuclease that cleaves the tails in 3' non-homologous tail removal (3' NHTR). Rad1-Rad10 is also an essential component of the nucleotide excision repair (NER) pathway. In both cases, Rad1-Rad10 requires protein partners for recruitment to the relevant DNA intermediate. Msh2-Msh3 and Saw1 recruit Rad1-Rad10 in 3' NHTR; Rad14 recruits Rad1-Rad10 in NER. We created two rad1 separation-of-function alleles, rad1R203A,K205A and rad1R218A; both are defective in 3' NHTR but functional in NER. In vitro, rad1R203A,K205A was impaired at multiple steps in 3' NHTR. The rad1R218A in vivo phenotype resembles that of msh2- or msh3-deleted cells; recruitment of rad1R218A-Rad10 to recombination intermediates is defective. Interactions among rad1R218A-Rad10 and Msh2-Msh3 and Saw1 are altered and rad1R218A-Rad10 interactions with RPA are compromised. We propose a model in which Rad1-Rad10 is recruited and positioned at the recombination intermediate through interactions, between Saw1 and DNA, Rad1-Rad10 and Msh2-Msh3, Saw1 and Msh2-Msh3 and Rad1-Rad10 and RPA. When any of these interactions is altered, 3' NHTR is impaired.

  7. Analysis of the rdd locus in chicken: a model for human retinitis pigmentosa.

    Science.gov (United States)

    Burt, David W; Morrice, David R; Lester, Douglas H; Robertson, Graeme W; Mohamed, Moin D; Simmons, Ian; Downey, Louise M; Thaung, Caroline; Bridges, Leslie R; Paton, Ian R; Gentle, Mike; Smith, Jacqueline; Hocking, Paul M; Inglehearn, Chris F

    2003-04-30

    To identify the locus responsible for the blind mutation rdd (retinal dysplasia and degeneration) in chickens and to further characterise the rdd phenotype. The eyes of blind and sighted birds were subjected to ophthalmic, morphometric and histopathological examination to confirm and extend published observations. Electroretinography was used to determine age of onset. Birds were crossed to create pedigrees suitable for genetic mapping. DNA samples were obtained and subjected to a linkage search. Measurement of IOP, axial length, corneal diameter, and eye weight revealed no gross morphological changes in the rdd eye. However, on ophthalmic examination, rdd homozygotes have a sluggish pupillary response, atrophic pecten, and widespread pigmentary disturbance that becomes more pronounced with age. Older birds also have posterior subcapsular cataracts. At three weeks of age, homozygotes have a flat ERG indicating severe loss of visual function. Pathological examination shows thinning of the RPE, ONL, photoreceptors and INL, and attenuation of the ganglion cell layer. From 77 classified backcross progeny, 39 birds were blind and 38 sighted. The rdd mutation was shown to be sex-linked and not autosomal as previously described. Linkage analysis mapped the rdd locus to a small region of the chicken Z chromosome with homologies to human chromosomes 5q and 9p. Ophthalmic, histopathologic, and electrophysiological observations suggest rdd is similar to human recessive retinitis pigmentosa. Linkage mapping places rdd in a region homologous to human chromosomes 9p and 5q. Candidate disease genes or loci include PDE6A, WGN1, and USH2C. This is the first use of genetic mapping in a chicken model of human disease.

  8. Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus.

    Science.gov (United States)

    Vakili, Hana; Jin, Yan; Cattini, Peter A

    2014-11-01

    Levels of pituitary growth hormone (GH), a metabolic homeostatic factor with strong lipolytic activity, are decreased in obese individuals. GH declines prior to the onset of weight gain in response to excess caloric intake and hyperinsulinemia; however, the mechanism by which GH is reduced is not clear. We used transgenic mice expressing the human GH (hGH) gene, GH1, to assess the effect of high caloric intake on expression as well as the local chromosome structure of the intact GH1 locus. Animals exposed to 3 days of high caloric intake exhibited hyperinsulinemia without hyperglycemia and a decrease in both hGH synthesis and secretion, but no difference in endogenous production of murine GH. Efficient GH1 expression requires a long-range intrachromosomal interaction between remote enhancer sequences and the proximal promoter region through "looping" of intervening chromatin. High caloric intake disrupted this interaction and decreased both histone H3/H4 hyperacetylation and RNA polymerase II occupancy at the GH1 promoter. Incorporation of physical activity muted the effects of excess caloric intake on insulin levels, GH1 promoter hyperacetylation, chromosomal architecture, and expression. These results indicate that energy homeostasis alters postnatal hGH synthesis through dynamic changes in the 3-dimensional chromatin structure of the GH1 locus, including structures required for cell type specificity during development.

  9. IMMUNOHISTOCHEMICAL STUDY OF MSH2, MSH6, PMS2, MLH1 IN EVALUATION OF DIFFERENTIATION GRADE OF COLON ADENOCARCINOMA

    Directory of Open Access Journals (Sweden)

    G. A. Raskin

    2015-01-01

    Full Text Available Microsatellite instability is associated with dysfunction of the MSH2, MLH1, PMS2 and MSH6 genes, which participate in the repair of unpaired nucleotides of DNA. It is known that microsatellite instability is an independent prognostic factor in determining the differentiation grade of colon cancer. The use of immunohistochemistry to study the repair system of unpaired nucleotides has its own characteristics and limitations. Materials and methods. The study included 39 patients with colon adenocarcinoma. Moderately-differentiated colon adenocarcinoma was the most common histological type (72 %. There were 8 % of well-differentiated and 12 % poorly-differentiated carcinomas. Immunohistochemical analysis of SH2, MSH6, PMS2 and MLH1 proteins was done according to the standard protocol. Results. Out of 39 cases, 6 (15 % had loss of expression of at least one of the studied proteins. Out of these 6 cases with indirect signs of MSI-H, 3 were poorlydifferentiated, 1 was mucinous and 2 were moderately differentiated adenocarcinomas. Conclusion. Thus, immunohistochemical analysis of DNA repair genes can be used to determine the histological differentiation of colon adenocarcinoma.

  10. Mlh1-Mlh3, a Meiotic Crossover and DNA Mismatch Repair Factor, Is a Msh2-Msh3-stimulated Endonuclease*

    Science.gov (United States)

    Rogacheva, Maria V.; Manhart, Carol M.; Chen, Cheng; Guarne, Alba; Surtees, Jennifer; Alani, Eric

    2014-01-01

    Crossing over between homologous chromosomes is initiated in meiotic prophase in most sexually reproducing organisms by the appearance of programmed double strand breaks throughout the genome. In Saccharomyces cerevisiae the double-strand breaks are resected to form three prime single-strand tails that primarily invade complementary sequences in unbroken homologs. These invasion intermediates are converted into double Holliday junctions and then resolved into crossovers that facilitate homolog segregation during Meiosis I. Work in yeast suggests that Msh4-Msh5 stabilizes invasion intermediates and double Holliday junctions, which are resolved into crossovers in steps requiring Sgs1 helicase, Exo1, and a putative endonuclease activity encoded by the DNA mismatch repair factor Mlh1-Mlh3. We purified Mlh1-Mlh3 and showed that it is a metal-dependent and Msh2-Msh3-stimulated endonuclease that makes single-strand breaks in supercoiled DNA. These observations support a direct role for an Mlh1-Mlh3 endonuclease activity in resolving recombination intermediates and in DNA mismatch repair. PMID:24403070

  11. Germ-line mutations at a mouse ESTR (Pc-3) locus and human microsatellite loci

    International Nuclear Information System (INIS)

    Ryo, Haruko; Nakajima, Hiroo; Nomura, Taisei

    2006-01-01

    We examined the use of the mouse Pc-3 ESTR (expanded simple tandem repeat) locus and 72 human microsatellite loci as potentially sensitive biomarkers for mutagenic exposures to germ cells in mice and humans respectively. In the mouse work, we treated male mice with TCDD (2, 3, 7, 8-tetrachlo-rodibenzo-p-dioxin; a chemical known to induce congenital anomalies in humans and mice) and, analysed the F 1 fetuses for Pc-3 mutations. Although the incidence of anomalies was higher in the TCDD group, there were no induced mutations. However, respiratory distress syndrome (RDS) was observed in 3 of 7 fetuses born to male mice which were treated with TCDD and which showed abnormal length of Pc-3 allele. In the human studies, the children of Chernobyl liquidators were examined for mutations at a total of 72 (31 autosomal, 1 X-linked and 40 Y-linked) microsatellite loci. This study was prompted by earlier findings of increases in microsatellite mutations in barn swallows and wheat in the highly contaminated areas after the Chernobyl accident. We examined 64 liquidator families (70 children) and 66 control families (70 children). However, no increases in mutation rates were found. The estimated mean dose to the liquidators was about 39 mSv and this might be one possible reason why no increases of mutations could be found. (author)

  12. Methylation and Transcripts Expression at the Imprinted GNAS Locus in Human Embryonic and Induced Pluripotent Stem Cells and Their Derivatives

    Directory of Open Access Journals (Sweden)

    Virginie Grybek

    2014-09-01

    Full Text Available Data from the literature indicate that genomic imprint marks are disturbed in human pluripotent stem cells (PSCs. GNAS is an imprinted locus that produces one biallelic (Gsα and four monoallelic (NESP55, GNAS-AS1, XLsα, and A/B transcripts due to differential methylation of their promoters (DMR. To document imprinting at the GNAS locus in PSCs, we studied GNAS locus DMR methylation and transcript (NESP55, XLsα, and A/B expression in human embryonic stem cells (hESCs and human induced pluripotent stem cells (hiPSCs derived from two human fibroblasts and their progenies. Results showed that (1 methylation at the GNAS locus DMRs is DMR and cell line specific, (2 changes in allelic transcript expression can be independent of a change in allele-specific DNA methylation, and (3 interestingly, methylation at A/B DMR is correlated with A/B transcript expression. These results indicate that these models are valuable to study the mechanisms controlling GNAS methylation, factors involved in transcript expression, and possibly mechanisms involved in the pathophysiology of pseudohypoparathyroidism type 1B.

  13. Reciprocal hybrid joints demonstrate successive V-J rearrangements on the same chromosome in the human TCR gamma locus

    NARCIS (Netherlands)

    Alexandre, D.; Chuchana, P.; Roncarolo, M. G.; Yssel, H.; Spits, H.; Lefranc, G.; Lefranc, M. P.

    1991-01-01

    Novel variable (V)--joining (J) gene rearrangements are described in the human T cell receptor gamma locus, in which, on the one hand, the V3 variable gene is joined to the heptamer--nonamer recombination signals of the J1 segment and, on the other hand, the J1 segment is joined to the V3

  14. Locus Reference Genomic sequences: An improved basis for describing human DNA variants

    KAUST Repository

    Dalgleish, Raymond; Flicek, Paul; Cunningham, Fiona; Astashyn, Alex; Tully, Raymond E; Proctor, Glenn; Chen, Yuan; McLaren, William M; Larsson, Pontus; Vaughan, Brendan W; Bé roud, Christophe; Dobson, Glen; Lehvä slaiho, Heikki; Taschner, Peter EM; den Dunnen, Johan T; Devereau, Andrew; Birney, Ewan; Brookes, Anthony J; Maglott, Donna R

    2010-01-01

    As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specifi c purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-fi le record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)- approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants aff ecting human health. Further information can be found on the LRG web site (http://www.lrg-sequence.org). 2010 Dalgleish et al.; licensee BioMed Central Ltd.

  15. Locus Reference Genomic sequences: An improved basis for describing human DNA variants

    KAUST Repository

    Dalgleish, Raymond

    2010-04-15

    As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specifi c purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-fi le record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)- approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants aff ecting human health. Further information can be found on the LRG web site (http://www.lrg-sequence.org). 2010 Dalgleish et al.; licensee BioMed Central Ltd.

  16. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

    Science.gov (United States)

    Schneider, Nayê Balzan; Pastor, Tatiane; Paula, André Escremim de; Achatz, Maria Isabel; Santos, Ândrea Ribeiro Dos; Vianna, Fernanda Sales Luiz; Rosset, Clévia; Pinheiro, Manuela; Ashton-Prolla, Patricia; Moreira, Miguel Ângelo Martins; Palmero, Edenir Inêz

    2018-05-01

    Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice-site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one-third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  17. Strengthening Locus Standi in Human Rights Litigation in Zimbabwe: An analysis of the Provisions in the New Zimbabwean Constitution

    Directory of Open Access Journals (Sweden)

    Lovemore Chiduza

    2016-05-01

    Full Text Available Zimbabweans have been both victims of and witnesses to serious human rights violations over the years. Though there is wide agreement and speculation that the state and its agencies are the perpetrators of these atrocities, they have largely remained unprosecuted and unpunished. Such impunity is inter alia the result of ineffective law enforcement mechanisms and institutions as well as the lack of capacity and legal knowledge of victims to approach the courts and seek redress. These factors negatively affected the protection of human rights and access to justice in Zimbabwe. Although the Lancaster House Constitution contained a Declaration of Rights, its enforcement mechanisms, particularly those relating to locus standi (legal standing, posed a great challenge to human rights litigation in Zimbabwe. This is so because the Lancaster House Constitution adopted the traditional common law approach to standing. Under this approach it was required that an individual must have a "personal, direct or substantial interest" in a matter in order to have standing. The Lancaster House Constitution failed to recognise the importance of broader rules of standing, which would accommodate public interest litigation, specifically for protecting human rights. Contrary to this, the new Constitution of Zimbabwe (2013 broadens the rules of standing in order to enhance access to the courts. This paper analyses the new approach to standing under the new constitutional dispensation in Zimbabwe. To this end, the discussion commences with an elucidation of the concept of locus standi and its link to access to justice. This is followed by an analysis of locus standi under the Lancaster House Constitution. Since the new approach in Zimbabwe is greatly informed by the South African approach to locus standi, a brief analysis of standing in South Africa is made. The paper concludes with a discussion of the approach to locus standi under the new constitution with a view to

  18. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.

    Science.gov (United States)

    Levy, Daniel; Neuhausen, Susan L; Hunt, Steven C; Kimura, Masayuki; Hwang, Shih-Jen; Chen, Wei; Bis, Joshua C; Fitzpatrick, Annette L; Smith, Erin; Johnson, Andrew D; Gardner, Jeffrey P; Srinivasan, Sathanur R; Schork, Nicholas; Rotter, Jerome I; Herbig, Utz; Psaty, Bruce M; Sastrasinh, Malinee; Murray, Sarah S; Vasan, Ramachandran S; Province, Michael A; Glazer, Nicole L; Lu, Xiaobin; Cao, Xiaojian; Kronmal, Richard; Mangino, Massimo; Soranzo, Nicole; Spector, Tim D; Berenson, Gerald S; Aviv, Abraham

    2010-05-18

    Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

  19. Molecular analysis of the human β-globin locus activation region

    International Nuclear Information System (INIS)

    Forrester, W.C.; Novak, U.; Gelinas, R.; Groudine, M.

    1989-01-01

    Recently, DNA sequences containing four erythroid-specific DNase I hypersensitive sites within 20 kilobases 5' of the human ε-globin gene have been identified as an important cis-acting regulatory element, the locus activation region (LAR). Subfragments of the LAR, containing either all or only the two 5' or two 3' hypersensitive sites were linked to the human β-globin gene and analyzed for their effect on globin gene expression in stably transformed mouse erythroleukemia (MEL) cells. Constructs containing all four of the hypersensitive sites increase β-gobin mRNA levels 8- to 13-fold, while constructs with only the 5' or 3' sites increase globin expression to a lesser extent. No effect was seen when the constructs were assayed in 3T3 fibroblasts. All of the LAR derivatives form hypersensitive sites at the corresponding sequence position in MEL cells prior to and after induction of MEL cell differentiation. However, in 3T3 fibroblasts only the hypersensitive site corresponding to the previously described erythroid-specific -10.9 site was formed

  20. Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus

    Directory of Open Access Journals (Sweden)

    Zongyang Mou

    2015-11-01

    Full Text Available Brain-derived neurotrophic factor (BDNF plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001 and greater adiposity in both adult and pediatric cohorts (p values < 0.05. We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

  1. DNA methylation-histone modification relationships across the desmin locus in human primary cells

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    Clelland Gayle K

    2009-05-01

    Full Text Available Abstract Background We present here an extensive epigenetic analysis of a 500 kb region, which encompasses the human desmin gene (DES and its 5' locus control region (LCR, the only muscle-specific transcriptional regulatory element of this type described to date. These data complement and extend Encyclopaedia of DNA Elements (ENCODE studies on region ENr133. We analysed histone modifications and underlying DNA methylation patterns in physiologically relevant DES expressing (myoblast/myotube and non-expressing (peripheral blood mononuclear primary human cells. Results We found that in expressing myoblast/myotube but not peripheral blood mononuclear cell (PBMC cultures, histone H4 acetylation displays a broadly distributed enrichment across a gene rich 200 kb region whereas H3 acetylation localizes at the transcriptional start site (TSS of genes. We show that the DES LCR and TSS of DES are enriched with hyperacetylated domains of acetylated histone H3, with H3 lysine 4 di- and tri-methylation (H3K4me2 and me3 exhibiting a different distribution pattern across this locus. The CpG island that extends into the first intron of DES is methylation-free regardless of the gene's expression status and in non-expressing PBMCs is marked with histone H3 lysine 27 tri-methylation (H3K27me3. Conclusion Overall, our results constitute the first study correlating patterns of histone modifications and underlying DNA methylation of a muscle-specific LCR and its associated downstream gene region whilst additionally placing this within a much broader genomic context. Our results clearly show that there are distinct patterns of histone H3 and H4 acetylation and H3 methylation at the DES LCR, promoter and intragenic region. In addition, the presence of H3K27me3 at the DES methylation-free CpG only in non-expressing PBMCs may serve to silence this gene in non-muscle tissues. Generally, our work demonstrates the importance of using multiple, physiologically relevant

  2. Hsp27, Hsp70 and mismatch repair proteins hMLH1 and hMSH2 expression in peripheral blood lymphocytes from healthy subjects and cancer patients.

    Science.gov (United States)

    Nadin, Silvina Beatriz; Vargas-Roig, Laura M; Drago, Gisela; Ibarra, Jorge; Ciocca, Daniel R

    2007-07-08

    Mismatch repair (MMR) deficiency and higher expression levels of heat shock proteins (Hsps) have been implicated with drug resistance to topoisomerase II poisons (doxorubicin) and to platinum compounds (cisplatin). This study was designed to determine individual influences of doxorubicin and cisplatin treatment on the expression of Hsp27, Hsp70, hMLH1 and hMSH2 proteins and in the DNA damage status in peripheral blood lymphocytes (PBLs). In addition, we studied whether these proteins and the DNA damage correlated with the survival of cancer patients. PBLs from 10 healthy donors and 25 cancer patients (before and after three cycles of chemotherapy) were exposed to in vitro treatments: C (control), HS (heat shock at 42 degrees C), Do or Pt (doxorubicin or cisplatin alone), and HS+Do or HS+Pt (heat shock+doxorubicin or heat shock+cisplatin). PBLs were collected at time 0 (T0: immediately after drug treatment) and after 24h of repair (T24). Hsp27, Hsp70, hMLH1 and hMSH2 were studied by immunocytochemistry and the DNA damage by alkaline comet assay. Immunofluorescence studies and confocal microscopy revealed that hMLH1 and hMSH2 colocalized with Hsp27 and Hsp72 (inducible form of Hsp70). hMLH1 and hMSH2 were significantly induced by Pt and HS+Pt at T24 in cancer patients, but only modestly influenced by Do. Cancer patients presented higher basal expression of total and nuclear Hsp27 and Hsp70 than controls, and these proteins were also increased by HS, Do and HS+Do. The Hsp70 induction by Pt and HS+Pt was noted in cancer patients, especially nuclear Hsp70. In cancer patients, basal DNA damage was slightly higher than in healthy persons; and after Pt and HS+Pt treatments, DNA migration and number of apoptotic cells were higher than controls. Hsps accomplished a cytoprotective function in pre-chemotherapy PBLs (HS before Do or Pt), but not in post-chemotherapy samples. In Pt-treated patients the ratio N/C (nuclear/cytoplasmic) of Hsp27 was related to disease free survival

  3. Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics

    DEFF Research Database (Denmark)

    Koutnikova, Hana; Laakso, Markku; Lu, Lu

    2009-01-01

    complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest......Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27...... recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897...

  4. Sterile DJH rearrangements reveal that distance between gene segments on the human Ig H chain locus influences their ability to rearrange

    DEFF Research Database (Denmark)

    Hansen, Tina Østergaard; Lange, Anders Blaabjerg; Barington, Torben

    2015-01-01

    Rearrangement of the Ig locus occurs in two steps. First, a JH gene is rearranged to a D gene followed by a VH gene rearranging to the DJH rearrangement. By next generation sequencing, we analyzed 9969 unique DJH rearrangements and 5919 unique VHDJH rearrangements obtained from peripheral blood B...... frequently than JH locus distal D genes, whereas VH locus proximal D genes were observed more frequently in nonproductive VHDJH rearrangements. We further demonstrate that the distance between VH, D, and JH gene segments influence their ability to rearrange within the human Ig locus....

  5. MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma

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    Sarver Aaron L

    2013-01-01

    Full Text Available Abstract Background Deregulation of microRNA (miRNA transcript levels has been observed in many types of tumors including osteosarcoma. Molecular pathways regulated by differentially expressed miRNAs may contribute to the heterogeneous tumor behaviors observed in naturally occurring cancers. Thus, tumor-associated miRNA expression may provide informative biomarkers for disease outcome and metastatic potential in osteosarcoma patients. We showed previously that clusters of miRNAs at the 14q32 locus are downregulated in human osteosarcoma. Methods Human and canine osteosarcoma patient’s samples with clinical follow-up data were used in this study. We used bioinformatics and comparative genomics approaches to identify miRNA based prognostic biomarkers in osteosarcoma. Kaplan-Meier survival curves and Whitney Mann U tests were conducted for validating the statistical significance. Results Here we show that an inverse correlation exists between aggressive tumor behavior (increased metastatic potential and accelerated time to death and the residual expression of 14q32 miRNAs (using miR-382 as a representative of 14q32 miRNAs in a series of clinically annotated samples from human osteosarcoma patients. We also show a comparable decrease in expression of orthologous 14q32 miRNAs in canine osteosarcoma samples, with conservation of the inverse correlation between aggressive behavior and expression of orthologous miRNA miR-134 and miR-544. Conclusions We conclude that downregulation of 14q32 miRNA expression is an evolutionarily conserved mechanism that contributes to the biological behavior of osteosarcoma, and that quantification of representative transcripts from this family, such as miR-382, miR-134, and miR-544, provide prognostic and predictive markers that can assist in the management of patients with this disease.

  6. MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma

    Science.gov (United States)

    2013-01-01

    Background Deregulation of microRNA (miRNA) transcript levels has been observed in many types of tumors including osteosarcoma. Molecular pathways regulated by differentially expressed miRNAs may contribute to the heterogeneous tumor behaviors observed in naturally occurring cancers. Thus, tumor-associated miRNA expression may provide informative biomarkers for disease outcome and metastatic potential in osteosarcoma patients. We showed previously that clusters of miRNAs at the 14q32 locus are downregulated in human osteosarcoma. Methods Human and canine osteosarcoma patient’s samples with clinical follow-up data were used in this study. We used bioinformatics and comparative genomics approaches to identify miRNA based prognostic biomarkers in osteosarcoma. Kaplan-Meier survival curves and Whitney Mann U tests were conducted for validating the statistical significance. Results Here we show that an inverse correlation exists between aggressive tumor behavior (increased metastatic potential and accelerated time to death) and the residual expression of 14q32 miRNAs (using miR-382 as a representative of 14q32 miRNAs) in a series of clinically annotated samples from human osteosarcoma patients. We also show a comparable decrease in expression of orthologous 14q32 miRNAs in canine osteosarcoma samples, with conservation of the inverse correlation between aggressive behavior and expression of orthologous miRNA miR-134 and miR-544. Conclusions We conclude that downregulation of 14q32 miRNA expression is an evolutionarily conserved mechanism that contributes to the biological behavior of osteosarcoma, and that quantification of representative transcripts from this family, such as miR-382, miR-134, and miR-544, provide prognostic and predictive markers that can assist in the management of patients with this disease. PMID:23311495

  7. The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons.

    Science.gov (United States)

    Finta, C; Zaphiropoulos, P G

    2000-12-30

    Using a bacterial artificial chromosome (BAC) clone, we have mapped the human cytochrome P450 3A (CYP3A) locus containing the genes encoding for CYP3A4, CYP3A5 and CYP3A7. The genes lie in a head-to-tail orientation in the order of 3A4, 3A7 and 3A5. In both intergenic regions (3A4-3A7 and 3A7-3A5), we have detected several additional cytochrome P450 3A exons, forming two CYP3A pseudogenes. These pseudogenes have the same orientation as the CYP3A genes. To our surprise, a 3A7 mRNA species has been detected in which the exons 2 and 13 of one of the pseudogenes (the one that is downstream of 3A7) are spliced after the 3A7 terminal exon. This results in an mRNA molecule that consists of the 13 3A7 exons and two additional exons at the 3' end. The additional two exons originating from the pseudogene are in an altered reading frame and consequently have the capability to code a completely different amino acid sequence than the canonical CYP3A exons 2 and 13. These findings may represent a generalized evolutionary process with genes having the potential to capture neighboring sequences and use them as functional exons.

  8. TALE nickase mediates high efficient targeted transgene integration at the human multi-copy ribosomal DNA locus.

    Science.gov (United States)

    Wu, Yong; Gao, Tieli; Wang, Xiaolin; Hu, Youjin; Hu, Xuyun; Hu, Zhiqing; Pang, Jialun; Li, Zhuo; Xue, Jinfeng; Feng, Mai; Wu, Lingqian; Liang, Desheng

    2014-03-28

    Although targeted gene addition could be stimulated strikingly by a DNA double strand break (DSB) created by either zinc finger nucleases (ZFNs) or TALE nucleases (TALENs), the DSBs are really mutagenic and toxic to human cells. As a compromised solution, DNA single-strand break (SSB) or nick has been reported to mediate high efficient gene addition but with marked reduction of random mutagenesis. We previously demonstrated effective targeted gene addition at the human multicopy ribosomal DNA (rDNA) locus, a genomic safe harbor for the transgene with therapeutic potential. To improve the transgene integration efficiency by using TALENs while lowering the cytotoxicity of DSBs, we created both TALENs and TALE nickases (TALENickases) targeting this multicopy locus. A targeting vector which could integrate a GFP cassette at the rDNA locus was constructed and co-transfected with TALENs or TALENickases. Although the fraction of GFP positive cells using TALENs was greater than that using TALENickases during the first few days after transfection, it reduced to a level less than that using TALENickases after continuous culture. Our findings showed that the TALENickases were more effective than their TALEN counterparts at the multi-copy rDNA locus, though earlier studies using ZFNs and ZFNickases targeting the single-copy loci showed the reverse. Besides, TALENickases mediated the targeted integration of a 5.4 kb fragment at a frequency of up to 0.62% in HT1080 cells after drug selection, suggesting their potential application in targeted gene modification not being limited at the rDNA locus. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Signatures of natural selection at the FTO (fat mass and obesity associated locus in human populations.

    Directory of Open Access Journals (Sweden)

    Xuanshi Liu

    Full Text Available Polymorphisms in the first intron of FTO have been robustly replicated for associations with obesity. In the Sorbs, a Slavic population resident in Germany, the strongest effect on body mass index (BMI was found for a variant in the third intron of FTO (rs17818902. Since this may indicate population specific effects of FTO variants, we initiated studies testing FTO for signatures of selection in vertebrate species and human populations.First, we analyzed the coding region of 35 vertebrate FTO orthologs with Phylogenetic Analysis by Maximum Likelihood (PAML, ω = dN/dS to screen for signatures of selection among species. Second, we investigated human population (Europeans/CEU, Yoruba/YRI, Chinese/CHB, Japanese/JPT, Sorbs SNP data for footprints of selection using DnaSP version 4.5 and the Haplotter/PhaseII. Finally, using ConSite we compared transcription factor (TF binding sites at sequences harbouring FTO SNPs in intron three.PAML analyses revealed strong conservation in coding region of FTO (ω<1. Sliding-window results from population genetic analyses provided highly significant (p<0.001 signatures for balancing selection specifically in the third intron (e.g. Tajima's D in Sorbs = 2.77. We observed several alterations in TF binding sites, e.g. TCF3 binding site introduced by the rs17818902 minor allele.Population genetic analysis revealed signatures of balancing selection at the FTO locus with a prominent signal in intron three, a genomic region with strong association with BMI in the Sorbs. Our data support the hypothesis that genes associated with obesity may have been under evolutionary selective pressure.

  10. Deletional rearrangement in the human T-cell receptor α-chain locus

    International Nuclear Information System (INIS)

    de Villartay, J.P.; Lewis, D.; Hockett, R.; Waldmann, T.A.; Korsmeyer, S.J.; Cohen, D.I.

    1987-01-01

    The antigen-specific receptor on the surface of mature T lymphocytes is a heterodimer consisting of polypeptides termed α and β. In the course of characterizing human T-cell tumors with an immature (CD4 - , CD8 - ) surface phenotype, the authors detected a 2-kilobase α-related transcript. Analysis of cDNA clones corresponding to this transcript established that a genetic element (which they call TEA, for T early α) located between the α-chain variable- and joining-region genes had been spliced to the α constant region. The TEA transcript is present early in thymocyte ontogeny, and its expression declines during T-cell maturation. More important, the TEA area functions as an active site for rearrangement within the α gene locus. Blot hybridization of restriction enzyme-digested DNA with a TEA probe revealed a narrowly limited pattern of rearrangement in polyclonal thymic DNA, surprisingly different from the pattern expected for the mature α gene with its complex diversity. These DNA blots also showed that TEA is generally present in the germ-line configuration in cells expressing the γδ heterodimeric receptor and is deleted from mature (αβ-expressing) T-lymphocyte tumors and lines. Moreover, the TEA transcript lacked a long open reading frame for protein but instead possessed multiple copies of a repetitive element resembling those utilized in the heavy-chain class switch of the immunoglobulin genes. The temporal nature of the rearrangements and expression detected by TEA suggests that this recombination could mediate a transition between immature (γδ-expressing) T cells and mature (αβ-expressing) T cells

  11. Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice.

    Science.gov (United States)

    Gillis, Caitlin M; Jönsson, Friederike; Mancardi, David A; Tu, Naxin; Beutier, Héloïse; Van Rooijen, Nico; Macdonald, Lynn E; Murphy, Andrew J; Bruhns, Pierre

    2017-04-01

    Anaphylaxis can proceed through distinct IgE- or IgG-dependent pathways, which have been investigated in various mouse models. We developed a novel mouse strain in which the human low-affinity IgG receptor locus, comprising both activating (hFcγRIIA, hFcγRIIIA, and hFcγRIIIB) and inhibitory (hFcγRIIB) hFcγR genes, has been inserted into the equivalent murine locus, corresponding to a locus swap. We sought to determine the capabilities of hFcγRs to induce systemic anaphylaxis and identify the cell types and mediators involved. hFcγR expression on mouse and human cells was compared to validate the model. Passive systemic anaphylaxis was induced by injection of heat-aggregated human intravenous immunoglobulin and active systemic anaphylaxis after immunization and challenge. Anaphylaxis severity was evaluated based on hypothermia and mortality. The contribution of receptors, mediators, or cell types was assessed based on receptor blockade or depletion. The human-to-mouse low-affinity FcγR locus swap engendered hFcγRIIA/IIB/IIIA/IIIB expression in mice comparable with that seen in human subjects. Knock-in mice were susceptible to passive and active anaphylaxis, accompanied by downregulation of both activating and inhibitory hFcγR expression on specific myeloid cells. The contribution of hFcγRIIA was predominant. Depletion of neutrophils protected against hypothermia and mortality. Basophils contributed to a lesser extent. Anaphylaxis was inhibited by platelet-activating factor receptor or histamine receptor 1 blockade. Low-affinity FcγR locus-switched mice represent an unprecedented model of cognate hFcγR expression. Importantly, IgG-related anaphylaxis proceeds within a native context of activating and inhibitory hFcγRs, indicating that, despite robust hFcγRIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

  12. Characterization of Pathogenic Human MSH2 Missense Mutations Using Yeast as a Model System: A Laboratory Course in Molecular Biology

    Science.gov (United States)

    Gammie, Alison E.; Erdeniz, Naz

    2004-01-01

    This work describes the project for an advanced undergraduate laboratory course in cell and molecular biology. One objective of the course is to teach students a variety of cellular and molecular techniques while conducting original research. A second objective is to provide instruction in science writing and data presentation by requiring…

  13. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas.

    Science.gov (United States)

    Felsberg, Jörg; Thon, Niklas; Eigenbrod, Sabina; Hentschel, Bettina; Sabel, Michael C; Westphal, Manfred; Schackert, Gabriele; Kreth, Friedrich Wilhelm; Pietsch, Torsten; Löffler, Markus; Weller, Michael; Reifenberger, Guido; Tonn, Jörg C

    2011-08-01

    Epigenetic silencing of the O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care. Copyright © 2011 UICC.

  14. Immunohistochemical null-phenotype for mismatch repair proteins in colonic carcinoma associated with concurrent MLH1 hypermethylation and MSH2 somatic mutations.

    Science.gov (United States)

    Wang, Tao; Stadler, Zsofia K; Zhang, Liying; Weiser, Martin R; Basturk, Olca; Hechtman, Jaclyn F; Vakiani, Efsevia; Saltz, Lenard B; Klimstra, David S; Shia, Jinru

    2018-04-01

    Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient's age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.

  15. Genetic characterization of human-pathogenic Cyclospora cayetanensis parasites from three endemic regions at the 18S ribosomal RNA locus.

    Science.gov (United States)

    Sulaiman, Irshad M; Ortega, Ynes; Simpson, Steven; Kerdahi, Khalil

    2014-03-01

    Cyclospora cayetanensis is an apicocomplexan parasite that infects the gastrointestinal tract and causes acute diarrheal disease in humans. In recent years, this human-pathogenic parasite has led to several foodborne outbreaks in the United States and Canada, mostly associated with imported produce. Understanding the biology and epidemiology of C. cayetanensis is difficult because little is known about its origin, possible zoonotic reservoirs, and genetic relationships with other coccidian parasites. Recently, we developed a 70kDa heat shock protein (HSP70) gene based nested PCR protocol for detection of C. cayetanensis parasite and sequenced the PCR products of 16 human isolates from Nepal, Mexico, and Peru. In this study, we have characterized the regions of 18S ribosomal RNA (rRNA) gene of 17 human C. cayetanensis isolates for molecular detection, and also to ascertain the genetic diversity of this parasite. The 18S rRNA primer sets were further tested by PCR amplification followed by nucleotide sequencing of the PCR amplified products of previously characterized C. cayetanensis isolates from three endemic regions at HSP70 locus. Although no genetic polymorphism was observed at the regions of HSP70 locus characterized in our previous study, the data analysis of this study revealed a minor genetic diversity at the 18S rRNA locus among the C. cayetanensis isolates. The 18S rRNA gene-based nested PCR protocol provides a useful genetic marker for the detection of C. cayetanensis parasite and confirms it as a genetically distinct species in genus Cyclospora. The results also supported lack of geographic segregation and existence of genetically homogeneous population for the C. cayetanensis parasites both at the HSP70 as well as at the18S rRNA loci. Published by Elsevier B.V.

  16. Genome scan identifies a locus affecting gamma-globin expression in human beta-cluster YAC transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Lin, S.D.; Cooper, P.; Fung, J.; Weier, H.U.G.; Rubin, E.M.

    2000-03-01

    Genetic factors affecting post-natal g-globin expression - a major modifier of the severity of both b-thalassemia and sickle cell anemia, have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human g-globin. To model the human b-cluster in mice, with the goal of screening for loci affecting human g-globin expression in vivo, we introduced a human b-globin cluster YAC transgene into the genome of FVB mice . The b-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) g allele resulting in postnatal expression of human g-globin in transgenic mice. The level of human g-globin for various F1 hybrids derived from crosses between the FVB transgenics and other inbred mouse strains was assessed. The g-globin level of the C3HeB/FVB transgenic mice was noted to be significantly elevated. To map genes affecting postnatal g-globin expression, a 20 centiMorgan (cM) genome scan of a C3HeB/F VB transgenics [prime] FVB backcross was performed, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within a 2.2 cM interval of mouse chromosome 1 at a LOD score of 4.2 that contributes 10.4% of variation in g-globin expression level. Combining transgenic modeling of the human b-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human g-globin expression in vivo.

  17. DNA locus HLA-DQ alpha polymorphism in human population of the north-eastern Poland.

    Science.gov (United States)

    Pepiński, W; Skawrońska, M; Janica, J

    1996-01-01

    Investigations on DNA polymorphism locus HLA-DQ alpha were carried out on a sample of 117 adult unrelated inhabitants from the north-eastern Poland. The polymerase chain reaction and the reverse dot-blot hybridisation were employed to detect 6 different HLA-DQ alpha alleles. Population data on 20 different genotypes served as a basis for statistic evaluation. The results of genotype analysis were in Hardy-Weinberg equilibrium. Other population data were compared.

  18. A T-cell specific transcriptional enhancer element 3' of Cα in the human T-cell receptor α locus

    International Nuclear Information System (INIS)

    Ho, Icheng; Yang, Lihsuan; Morle, G.; Leiden, J.M.

    1989-01-01

    A transcriptional enhancer element has been identified 4.5 kilobases 3' of C α (constant region α chain) in the human T-cell receptor (TCR) α-chain locus. This enhancer is active on both a TCR V α (variable region α chain) promoter and the minimal simian virus 40 promoter in TCR α/β Jurkat and EL4 cells but is inactive on a V α promoter TCR γ/δ PEER and Molt-13 cells, clone 13 B cells, and HeLa fibroblasts. The enhancer has been localized to a 116-base-pair BstXI/Dra I restriction enzyme fragment, which lacks immunoglobulin octamer and κB enhancer motifs but does contain a consensus cAMP-response element (CRE). DNase I footprint analyses demonstrated that the minimal enhancer contains two binding sites for Jurkat nuclear proteins. One of these sites corresponds to the CRE, while the other does not correspond to a known transcriptional enhancer motif. These data support a model in which TCR α gene transcription is regulated by a unique set of cis-acting sequences and trans-acting factors, which are differentially active in cells of the TCR α/β lineage. In addition, the TCR α enhancer may play a role in activating oncogene expression in T-lymphoblastoid tumors that have previously been shown to display chromosomal translocations into the human TCR α locus

  19. [Immunohistochemical examination of MSH2, PMS2, MLH1, MSH6 compared with the analysis of microsatellite instability in colon adenocarcinoma].

    Science.gov (United States)

    Raskin, G A; Ianus, G A; Kornilov, A V; Orlova, R V; Petrov, S V; Protasova, A É; Pozharisskiĭ, K M; Imianitov, E N

    2014-01-01

    Adenocarcinoma of the colon in 10-20% is associated with microsatellite instability, which can occur both in sporadic cancers and in hereditary nonpolyposis colon cancer. Our analysis of 195 cases of adenocarcinoma of the colon showed that microsatellite instability (MSI-H) was found only in 1.5% of patients. Subsequent choice of patients with suspected hereditary Lynch syndrome led to the identification of additional 17 patients with microsatellite instability. They passed an analysis of genes of repair system of unpaired nucleotides of DNA. The study showed that immunohistochemical staining of MSH2, MSH6, MLH1, PMS2 could effectively conduct a preliminary screening of the Lynch syndrome but was unable to divide cases of sporadic and hereditary MSI-H colon cancer.

  20. Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH)

    DEFF Research Database (Denmark)

    Staaf, Johan; Törngren, Therese; Rambech, Eva

    2008-01-01

    Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic hybridizat......Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic...... deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged...... from several 100 kb, including large flanking regions, to rearrangements, allowing convenient design...

  1. Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families

    International Nuclear Information System (INIS)

    Thodi, Georgia; Fountzilas, George; Yannoukakos, Drakoulis; Fostira, Florentia; Sandaltzopoulos, Raphael; Nasioulas, George; Grivas, Anastasios; Boukovinas, Ioannis; Mylonaki, Maria; Panopoulos, Christos; Magic, Mirjana Brankovic

    2010-01-01

    Germline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The MLH1, MSH2 and MSH6 mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of MLH1, MSH2 and MSH6 mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort. Forty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines. Ten deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the MLH1 gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years. The mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect

  2. Identification of distal regulatory regions in the human alpha IIb gene locus necessary for consistent, high-level megakaryocyte expression.

    Science.gov (United States)

    Thornton, Michael A; Zhang, Chunyan; Kowalska, Maria A; Poncz, Mortimer

    2002-11-15

    The alphaIIb/beta3-integrin receptor is present at high levels only in megakaryocytes and platelets. Its presence on platelets is critical for hemostasis. The tissue-specific nature of this receptor's expression is secondary to the restricted expression of alphaIIb, and studies of the alphaIIb proximal promoter have served as a model of a megakaryocyte-specific promoter. We have examined the alphaIIb gene locus for distal regulatory elements. Sequence comparison between the human (h) and murine (m) alphaIIb loci revealed high levels of conservation at intergenic regions both 5' and 3' to the alphaIIb gene. Additionally, deoxyribonuclease (DNase) I sensitivity mapping defined tissue-specific hypersensitive (HS) sites that coincide, in part, with these conserved regions. Transgenic mice containing various lengths of the h(alpha)IIb gene locus, which included or excluded the various conserved/HS regions, demonstrated that the proximal promoter was sufficient for tissue specificity, but that a region 2.5 to 7.1 kb upstream of the h(alpha)IIb gene was necessary for consistent expression. Another region 2.2 to 7.4 kb downstream of the gene enhanced expression 1000-fold and led to levels of h(alpha)IIb mRNA that were about 30% of the native m(alpha)IIb mRNA level. These constructs also resulted in detectable h(alpha)IIb/m(beta)3 on the platelet surface. This work not only confirms the importance of the proximal promoter of the alphaIIb gene for tissue specificity, but also characterizes the distal organization of the alphaIIb gene locus and provides an initial localization of 2 important regulatory regions needed for the expression of the alphaIIb gene at high levels during megakaryopoiesis.

  3. Two human cDNA molecules coding for the Duchenne muscular dystrophy (DMD) locus are highly homologous

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, A.; Speer, A.; Billwitz, H. (Zentralinstitut fuer Molekularbiologie, Berlin-Buch (Germany Democratic Republic)); Cross, G.S.; Forrest, S.M.; Davies, K.E. (Univ. of Oxford (England))

    1989-07-11

    Recently the complete sequence of the human fetal cDNA coding for the Duchenne muscular dystrophy (DMD) locus was reported and a 3,685 amino acid long, rod-shaped cytoskeletal protein (dystrophin) was predicted as the protein product. Independently, the authors have isolated and sequenced different DMD cDNA molecules from human adult and fetal muscle. The complete 12.5 kb long sequence of all their cDNA clones has now been determined and they report here the nucleotide (nt) and amino acid (aa) differences between the sequences of both groups. The cDNA sequence comprises the whole coding region but lacks the first 110 nt from the 5{prime}-untranslated region and the last 1,417 nt of the 3{prime}-untranslated region. They have found 11 nt differences (approximately 99.9% homology) from which 7 occurred at the aa level.

  4. Conservation of the primary structure, organization, and function of the human and mouse β-globin locus-activating regions

    International Nuclear Information System (INIS)

    Moon, A.M.; Ley, T.J.

    1990-01-01

    DNA sequences located in a region 6-18 kilobases (kb) upstream from the human ε-globin gene are known as the locus-activating region (LAR) or dominant control region. This region is thought to play a key role in chromatin organization of the β-like globin gene cluster during erythroid development. Since the human β-globin LAR is functional in mice, the authors reasoned that critical LAR sequence elements might be conserved between mice and humans. They therefore cloned murine genomic sequences homologous to one portion of the human LAR. They found that this murine DNA fragment (mouse LAR site II) and sequences homologous to human LAR sites I and III are located upstream from the mouse β-like globin gene cluster and determined that their locations relative to the cluster are similar to that of their human counterparts. The homologous site II sequences are 70% identical between mice and humans over a stretch of ∼800 base pairs. These results suggest that primary structural elements endash and the spatial organization of these elements endash are important for function of the β-globin LAR

  5. Human β-globin locus control region: Analysis of the 5' DNase I hypersensitive site HS 2 in transgenic mice

    International Nuclear Information System (INIS)

    Caterina, J.J.; Ryan, T.M.; Pawlik, K.M.; Townes, T.M.; Brinster, R.L.; Behringer, R.R.; Palmiter, R.D.

    1991-01-01

    The human β-globin locus control region (LCR) is essential for high-level expression of human var-epsilon-, γ-, and β-globin genes. Developmentally stable DNase I hypersensitive sites (designated HS) mark sequences within this region that are important for LCR activity. A 1.9-kilobase (kb) fragment containing the 5' HS 2 site enhances human β-globin gene expression 100-fold in transgenic mice and also confers position-independent expression. To further define important sequences within this region, deletion mutations of the 1.9-kb fragment were introduced upstream of the human β-globin gene, and the constructs were tested for activity in transgenic mice. Although enhancer activity was gradually lost with deletion of both 5' and 3' sequences, a 373-base-pair (BP) fragment retained the ability to confer relative position-independent expression. Three prominent DNase I footprints were observed in this region with extracts from the human erythroleukemia cell line K-562, one of which contained duplicated binding sites for transcription factor AP-1 (activator protein 1). When the 1.9-kb fragment containing an 19-bp deletion of the AP-1 binding sites was tested in transgenic mice, enhancer activity decreased 20-fold but position-independent expression was retained

  6. The effects of human relations training on reported teacher stress, pupil control ideology and locus of control.

    Science.gov (United States)

    Hall, E; Hall, C; Abaci, R

    1997-12-01

    This study presents the reported outcomes of a two-year, part-time Masters' programme in human relations using an experiential learning methodology based mainly on humanistic psychological theory. The following hypotheses were examined. That as a result of the two-year programme: the experience of reported stress would be reduced; reported attitudes to student classroom control would shift from custodial to humanistic; there would be an increase in reports from participants of a sense of control over their lives; changes of behaviour in work, social settings and at home related to these three variables would be reported. Involved in the study were 42 experienced teachers. These included 32 women and 10 men, with an average age of 35, who worked in a wide range of educational institutions. Their learning style preferences were also considered as independent variables. A control group of 42 was established with similar demographic characteristics. Prior to the course, the experimental group and the control group were given the Maslach Burnout Inventory and the Pupil Control Ideology Form. In the early stages of the course, the experimental group completed the Kolb Learning Style Inventory and an informal measure of locus of control which was repeated at the end of the first year of the course. A sample of 32 from the experimental group were given semi-structured interviews relating to changes in their professional and personal lives. The results indicated that, following the training, there was a reduction in reported stress, indications of a more humanistic orientation towards pupil control and an increase in a sense of an internal locus of control. The quantitative data were confirmed by qualitative data generated from semi-structured interviews, which involved substantial reports of applications of the training in their professional and personal lives. These results provide support for including experiential human relations training as part of both the in

  7. CRISPR/Cas9-AAV Mediated Knock-in at NRL Locus in Human Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    Xianglian Ge

    2016-01-01

    Full Text Available Clustered interspaced short palindromic repeats (CRISPR/CRISPR-associated protein 9 (Cas9-mediated genome engineering technologies are sparking a new revolution in biological research. This technology efficiently induces DNA double strand breaks at the targeted genomic sequence and results in indel mutations by the error-prone process of nonhomologous end joining DNA repair or homologous recombination with a DNA repair template. The efficiency of genome editing with CRISPR/Cas9 alone in human embryonic stem cells is still low. Gene targeting with adeno-associated virus (AAV vectors has been demonstrated in multiple human cell types with maximal targeting frequencies without engineered nucleases. However, whether CRISPR/Cas9-mediated double strand breaks and AAV based donor DNA mediated homologous recombination approaches could be combined to create a novel CRISPR/Cas9-AAV genetic tool for highly specific gene editing is not clear. Here we demonstrate that using CRISPR/Cas9-AAV, we could successfully knock-in a DsRed reporter gene at the basic motifleucine zipper transcription factor (NRL locus in human embryonic stem cells. For the first time, this study provides the proof of principle that these two technologies can be used together. CRISPR/Cas9-AAV, a new genome editing tool, offers a platform for the manipulation of human genome.

  8. Complex rearrangements within the human J delta-C delta/J alpha-C alpha locus and aberrant recombination between J alpha segments

    NARCIS (Netherlands)

    Baer, R.; Boehm, T.; Yssel, H.; Spits, H.; Rabbitts, T. H.

    1988-01-01

    We have examined DNA rearrangements within a 120 kb cloned region of the human T cell receptor J delta-C delta/J alpha-C alpha locus. Three types of pattern emerge from an analysis of T cell lines and clones. Firstly, cells with two rearrangements within J delta-C delta; secondly, cells with one

  9. Unraveling of the polymorphic C lambda 2-C lambda 3 amplification and the Ke+Oz- polymorphism in the human Ig lambda locus

    NARCIS (Netherlands)

    M. van der Burg (Mirjam); B.H. Barendregt (Barbara); E.J. van Gastel-Mol (Ellen); T. Tümkaya (Talip); A.W. Langerak (Anton); J.J.M. van Dongen (Jacques)

    2002-01-01

    textabstractTwo polymorphisms of the human Ig(lambda) (IGL) locus have been described. The first polymorphism concerns a single, 2- or 3-fold amplification of 5.4 kb of DNA in the C(lambda)2-C(lambda)3 region. The second polymorphism is the Mcg(-)Ke(+)Oz(-) isotype, which has

  10. MboI RFLP at the human renin (ren) gene locus

    Energy Technology Data Exchange (ETDEWEB)

    Masharani, U; Frossard, P M

    1988-03-25

    1.5kb full length human renin cDNA was isolated from a human kidney cDNA library and subcloned into pUC9. MboI (GATC) detects a single two allele polymorphism with fragments at either 1.4kb or 1.0kb. The frequency was studied in 80 unrelated North American. The human renin gene was assigned to chromosome 1 by southern blot analysis of DNA from human-rodent somatic cell hybrids. Codominant segregation was observed in 1 family (7 individuals).

  11. The IGF2 Locus

    Science.gov (United States)

    Insulin-like growth factor 2 (IGF2) is a peptide hormone regulating various cellular processes such as proliferation and apoptosis. IGF2 is vital to embryo development. The IGF2 locus covers approximately 150-kb genomic region on human chromosome 11, containing two imprinted genes, IGF2 and H19, sha...

  12. Mismatch Repair Proteins and Microsatellite Instability in Colorectal Carcinoma (MLH1, MSH2, MSH6 and PMS2): Histopathological and Immunohistochemical Study.

    Science.gov (United States)

    Ismael, Nour El Hoda S; El Sheikh, Samar A; Talaat, Suzan M; Salem, Eman M

    2017-03-15

    Colorectal cancer (CRC) is one of the most common cancers worldwide. Microsatellite instability (MSI) is detected in about 15% of all colorectal cancers. CRC with MSI has particular characteristics such as improved survival rates and better prognosis. They also have a distinct sensitivity to the action of chemotherapy. The aim of the study was to detect microsatellite instability in a cohort of colorectal cancer Egyptian patients using the immunohistochemical expression of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Cases were divided into Microsatellite stable (MSS), Microsatellite unstable low (MSI-L) and Microsatellite unstable high (MSI-H). This Microsatellite stability status was correlated with different clinicopathological parameters. There was a statistically significant correlation between the age of cases, tumor site & grade and the microsatellite stability status. There was no statistically significant correlation between the gender of patients, tumor subtype, stage, mucoid change, necrosis, tumor borders, lymphocytic response, lymphovascular emboli and the microsatellite stability status. Testing for MSI should be done for all colorectal cancer patients, especially those younger than 50 years old, right sided and high-grade CRCs.

  13. Pvu-II RFLP at the human lipoprotein lipase (LPL) gene locus

    Energy Technology Data Exchange (ETDEWEB)

    Li, S; Oka, K; Galton, D; Stocks, J

    1988-03-25

    Human lipoprotein lipase (LPL) cDNA, 1.6 Kbp, was isolated from human adipose cDNA library and subcloned into Bam HI site of pIB131. Pvu-II identifies a two allele polymorphism with bands at 7.0 Kb, 4.4 Kb and 2.5 Kb. The frequency was studied in 34 caucasians. The gene was assigned to 8p22. Co-dominant inheritance was demonstrated in a 2 generation family.

  14. Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus.

    Science.gov (United States)

    Black, Holly A; Khan, Fayeza F; Tyson, Jess; Al Armour, John

    2014-07-21

    The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. However, obtaining spatial information at regions displaying extensive copy number variation, such as the DEFA1A3 locus, is complex, because of the difficulty in the phasing and assembly of these regions. The DEFA1A3 locus is intriguing in that it falls within a region of high linkage disequilibrium, despite its high variability in copy number (n = 3-16); hence, the mechanisms responsible for changes in copy number at this locus are unclear. In this study, a region flanking the DEFA1A3 locus was sequenced across 120 independent haplotypes with European ancestry, identifying five common classes of DEFA1A3 haplotype. Assigning DEFA1A3 class to haplotypes within the 1000 Genomes project highlights a significant difference in DEFA1A3 class frequencies between populations with different ancestry. The features of each DEFA1A3 class, for example, the associated DEFA1A3 copy numbers, were initially assessed in a European cohort (n = 599) and replicated in the 1000 Genomes samples, showing within-class similarity, but between-class and between-population differences in the features of the DEFA1A3 locus. Emulsion haplotype fusion-PCR was used to generate 61 structural haplotypes at the DEFA1A3 locus, showing a high within-class similarity in structure. Structural haplotypes across the DEFA1A3 locus indicate that intra-allelic rearrangement is the predominant mechanism responsible for changes in DEFA1A3 copy number, explaining the conservation of linkage disequilibrium across the locus. The identification of common structural haplotypes at the DEFA1A3 locus could aid studies into how DEFA1A3 copy number influences expression, which is currently unclear.

  15. Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome.

    Directory of Open Access Journals (Sweden)

    Abram Bunya Kamiza

    Full Text Available Lynch syndrome, caused by germline mutations in mismatch repair genes, is a predisposing factor for colorectal cancer (CRC. This retrospective cohort study investigated the risk factors associated with the development of CRC in patients with MLH1 and MSH2 germline mutations.In total, 301 MLH1 and MSH2 germline mutation carriers were identified from the Amsterdam criteria family registry provided by the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A Cox proportional hazard model was used to calculate the hazard ratios (HRs and 95% confidence intervals (CIs to determine the association between the risk factors and CRC development. A robust sandwich covariance estimation model was used to evaluate family dependence.Among the total cohort, subjects of the Hakka ethnicity exhibited an increased CRC risk (HR = 1.62, 95% CI = 1.09-2.34; however, those who performed regular physical activity exhibited a decreased CRC risk (HR = 0.62, 95% CI = 0.41-0.88. The CRC risk was enhanced in MLH1 germline mutation carriers, with corresponding HRs of 1.72 (95% CI = 1.16-2.55 and 0.54 (95% CI = 0.34-0.83 among subjects of the Hakka ethnicity and those who performed regular physical activity, respectively. In addition, the total cohort with a manual occupation had a 1.56 times higher CRC risk (95% CI = 1.07-2.27 than did that with a skilled occupation. Moreover, MSH2 germline mutation carriers with blood group type B exhibited an increased risk of CRC development (HR = 2.64, 95% CI = 1.06-6.58 compared with those with blood group type O.The present study revealed that Hakka ethnicity, manual occupation, and blood group type B were associated with an increased CRC risk, whereas regular physical activity was associated with a decreased CRC risk in MLH1 and MSH2 germline mutation carriers.

  16. Efficient CRISPR-Cas9-mediated generation of knockin human pluripotent stem cells lacking undesired mutations at the targeted locus.

    Science.gov (United States)

    Merkle, Florian T; Neuhausser, Werner M; Santos, David; Valen, Eivind; Gagnon, James A; Maas, Kristi; Sandoe, Jackson; Schier, Alexander F; Eggan, Kevin

    2015-05-12

    The CRISPR-Cas9 system has the potential to revolutionize genome editing in human pluripotent stem cells (hPSCs), but its advantages and pitfalls are still poorly understood. We systematically tested the ability of CRISPR-Cas9 to mediate reporter gene knockin at 16 distinct genomic sites in hPSCs. We observed efficient gene targeting but found that targeted clones carried an unexpectedly high frequency of insertion and deletion (indel) mutations at both alleles of the targeted gene. These indels were induced by Cas9 nuclease, as well as Cas9-D10A single or dual nickases, and often disrupted gene function. To overcome this problem, we designed strategies to physically destroy or separate CRISPR target sites at the targeted allele and developed a bioinformatic pipeline to identify and eliminate clones harboring deleterious indels at the other allele. This two-pronged approach enables the reliable generation of knockin hPSC reporter cell lines free of unwanted mutations at the targeted locus. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Human lactoferrin efficiently targeted into caprine beta-lactoglobulin locus with transcription activator-like effector nucleases

    Directory of Open Access Journals (Sweden)

    Yu-Guo Yuan

    2017-08-01

    Full Text Available Objective To create genetically modified goat as a biopharming source of recombinant human lacotoferrin (hLF with transcription activator-like effector nucleases. Methods TALENs and targeting vector were transferred into cultured fibroblasts to insert hLF cDNA in the goat beta-lactoglobulin (BLG locus with homology-directed repair. The gene targeted efficiency was checked using sequencing and TE7I assay. The bi-allelic gene targeted colonies were isolated and confirmed with polymerase chain reaction, and used as donor cells for somatic cell nuclear transfer (SCNT. Results The targeted efficiency for BLG gene was approximately 10%. Among 12 Bi-allelic gene targeted colonies, five were used in first round SCNT and 4 recipients (23% were confirmed pregnant at 30 d. In second round SCNT, 7 (53%, 4 (31%, and 3 (23% recipients were confirmed to be pregnant by ultrasound on 30 d, 60 d, and 90 d. Conclusion This finding signifies the combined use of TALENs and SCNT can generate bi-allelic knock-in fibroblasts that can be cloned in a fetus. Therefore, it might lay the foundation for transgenic hLF goat generation and possible use of their mammary gland as a bioreactor for large-scale production of recombinant hLF.

  18. Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.

    Science.gov (United States)

    Marafie, Makia J; Al-Awadi, Sadiqa; Al-Mosawi, Fatemah; Elshafey, Alaa; Al-Ali, Waleed; Al-Mulla, Fahd

    2009-01-01

    Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

  19. Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus

    OpenAIRE

    Black, Holly A; Khan, Fayeza F; Tyson, Jess; Armour, John AL

    2014-01-01

    Background The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. However, obtaining spatial information at regions displaying extensive copy number variation, such as the DEFA1A3 locus, is complex, because of the difficulty in the phasing and assembly of these regions. The DEFA1A3 locus is intriguing in that it falls within a reg...

  20. Tissue expression of MLH1, PMS2, MSH2, and MSH6 proteins and prognostic value of microsatellite instability in Wilms tumor: experience of 45 cases.

    Science.gov (United States)

    Diniz, Gulden; Aktas, Safiye; Cubuk, Cankut; Ortac, Ragip; Vergin, Canan; Olgun, Nur

    2013-05-01

    Although the importance of microsatellite instability (MSI) and mismatch repair genes (MMR) is strongly established in colorectal cancer seen in the Lynch syndrome, its significance has not been fully established in Wilms tumor (WT). The aim of this study was to determine the prognostic value of MSI and MMR proteins in WT. This study included 45 pediatric cases with nephroblastoma. Protein expression was analyzed by immunohistochemistry of archival tissue sections. Real-time PCR melting analysis and fluorescence capillary electrophoresis (FCE) were performed to evaluate the MSI markers BAT25, BAT26, NR21, NR24, MONO27, penta D, and penta C in DNA extracted from tumor and normal tissues. Lower levels of MSI were observed in six cases (13.3%). There were no statistically significant correlations between MSI and some clinical prognostic factors such as stage of the tumors, and survival rates. Nineteen tumors (42.2%) showed loss of protein expression of MLH1, PMS2, MSH2, or MSH6. MMR protein defects were correlated with size (P = .021), and stage (P = .019) of the tumor, and survival rates (P < .01).Similarly MSI was also correlated with the size of the tumor (P = .046). This study showed that a small proportion of WT might be associated with the presence of MSI, as is the case with defects of DNA mismatch repair genes in the pathogenesis of WT. However, there was no concordance with the frequency of tissue expression of MMR proteins and MSI. These findings suggest that MMR genes may play an important role in the development of WT via different pathways.

  1. ''Normal'' tissues from humans exposed to radium contain an alteration in the c-mos locus

    International Nuclear Information System (INIS)

    Huberman, E.; Schlenker, R.A.; Hardwick, J.P.

    1989-01-01

    The structures of a number of human proto-oncogenes from persons with internal systemic exposure to radium were analyzed by restriction enzyme digestion and southern blotting of their DNA. Two extra c-mos Eco R1 restriction-fragment-length bands of 5.0 kb and 5.5 kb were found in tissue DNA from six of seven individuals. The extra c-mos bands were detected in DNA from many, but not all, of the tissues of the individuals exposed to radium. Our results suggest that the c-mos restriction-fragment-length alterations (RFLA) found in individuals exposed to radium were induced rather than inherited, are epigenetic in origin, and most likely result from changes in the methylation of bases surrounding the single exon of the c-mos proto-oncogene. 7 refs., 3 figs., 2 tabs

  2. Population genetic evidence for positive and purifying selection acting at the human IFN-γ locus in Africa.

    Science.gov (United States)

    Campbell, Michael C; Smith, Lunden T; Harvey, Jayla

    2018-03-29

    Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-γ, or the evolutionary forces that have shaped patterns of diversity at this locus. To address this gap in knowledge, we examined sequence data from the IFN-γ gene in 1461 individuals from 15 worldwide populations. Our analyses uncovered novel patterns of variation in distinct African populations, including an excess of high frequency-derived alleles, unusually long haplotype structure surrounding the IFN-γ gene, and a "star-like" genealogy of African-specific haplotypes carrying variants previously associated with infectious disease. We also inferred a deep time to coalescence of variation at IFN-γ (~ 0.8 million years ago) and ancient ages for common polymorphisms predating the evolution of modern humans. Taken together, these results are congruent with a model of positive selection on standing variation in African populations. Furthermore, we inferred that common variants in intron 3 of IFN-γ are the likely targets of selection. In addition, we observed a paucity of non-synonymous substitutions relative to synonymous changes in the exons of IFN-γ in African and non-African populations, suggestive of strong purifying selection. Therefore, we contend that positive and purifying selection have influenced levels of diversity in different regions of IFN-γ, implying that these distinct genic regions are, or have been, functionally important. Overall, this study provides additional insights into the evolutionary events that have contributed to the frequency and distribution of alleles having a role in human health and disease.

  3. N-ethyl-N-nitrosourea-induced null mutation at the mouse Car-2 locus: An animal model for human carbonic anhydrase II deficiency syndrome

    International Nuclear Information System (INIS)

    Lewis, S.E.; Barnett, L.B.; Erickson, R.P.; Venta, P.J.; Tashian, R.E.

    1988-01-01

    Electrophoretic screening of (C57BL/6J x DBA/2J)F 1 progeny of male mice treated with N-ethyl-N-nitrosourea revealed a mouse that lacked the paternal carbonic anhydrase II (Ca II). Breeding tests showed that this trait was heritable and due to a null mutation at the Car-2 locus on chromosome 3. Like humans with the same inherited enzyme defect, animals homozygous for the new null allele are runted and have renal tubular acidosis. However, the prominent osteopetrosis found in humans with CA II deficiency could be detected even in very old homozygous null mice. A molecular analysis of the deficient mice shows that the mutant gene is not deleted and is transcribed. The CA II protein, which is normally expressed in most tissues, could not be detected by immunodiffusion analysis in any tissues of the CA II-deficient mice, suggesting a nonsense or a missense mutation at the Car-2 locus

  4. Tissue-specific expression of the human laminin alpha5-chain, and mapping of the gene to human chromosome 20q13.2-13.3 and to distal mouse chromosome 2 near the locus for the ragged (Ra) mutation

    DEFF Research Database (Denmark)

    Durkin, M E; Loechel, F; Mattei, M G

    1997-01-01

    , heart, lung, skeletal muscle, kidney, and pancreas. The human laminin alpha5-chain gene (LAMA5) was assigned to chromosome 20q13.2-q13.3 by in situ hybridization, and the mouse gene (Lama5) was mapped by linkage analysis to a syntonic region of distal chromosome 2, close to the locus for the ragged (Ra...

  5. HS5 of the human β-globin Locus Control Region: a developmental stage-specific border in erythroid cells.

    NARCIS (Netherlands)

    A. Wai (Albert); N. Gillemans (Nynke); S. Raguz-Bolognesi (Selina); S. Pruzina (Sara); G. Zafarana (Gaetano); D.N. Meijer (Dies); F.G. Grosveld (Frank); J.N.J. Philipsen (Sjaak)

    2003-01-01

    textabstractElements with insulator/border activity have been characterized most extensively in Drosophila melanogaster. In vertebrates, the first example of such an element was provided by a hypersensitive site of the chicken beta-globin locus, cHS4. It has been proposed that the homologous site in

  6. The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function

    Directory of Open Access Journals (Sweden)

    Wahlestedt Claes

    2007-03-01

    Full Text Available Abstract Background Mutations in the PTEN induced putative kinase 1 (PINK1 are implicated in early-onset Parkinson's disease. PINK1 is expressed abundantly in mitochondria rich tissues, such as skeletal muscle, where it plays a critical role determining mitochondrial structural integrity in Drosophila. Results Herein we characterize a novel splice variant of PINK1 (svPINK1 that is homologous to the C-terminus regulatory domain of the protein kinase. Naturally occurring non-coding antisense provides sophisticated mechanisms for diversifying genomes and we describe a human specific non-coding antisense expressed at the PINK1 locus (naPINK1. We further demonstrate that PINK1 varies in vivo when human skeletal muscle mitochondrial content is enhanced, supporting the idea that PINK1 has a physiological role in mitochondrion. The observation of concordant regulation of svPINK1 and naPINK1 during in vivo mitochondrial biogenesis was confirmed using RNAi, where selective targeting of naPINK1 results in loss of the PINK1 splice variant in neuronal cell lines. Conclusion Our data presents the first direct observation that a mammalian non-coding antisense molecule can positively influence the abundance of a cis-transcribed mRNA under physiological abundance conditions. While our analysis implies a possible human specific and dsRNA-mediated mechanism for stabilizing the expression of svPINK1, it also points to a broader genomic strategy for regulating a human disease locus and increases the complexity through which alterations in the regulation of the PINK1 locus could occur.

  7. Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome.

    Science.gov (United States)

    Berginc, Gasper; Bracko, Matej; Ravnik-Glavac, Metka; Glavac, Damjan

    2009-01-01

    Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.

  8. A two-locus DNA sequence database for typing plant and human pathogens within the Fusarium oxysporum species complex

    DEFF Research Database (Denmark)

    O'Donnell, Kerry; Gueidan, C; Sink, S

    2009-01-01

    We constructed a two-locus database, comprising partial translation elongation factor (EF-1alpha) gene sequences and nearly full-length sequences of the nuclear ribosomal intergenic spacer region (IGS rDNA) for 850 isolates spanning the phylogenetic breadth of the Fusarium oxysporum species compl...... of the IGS rDNA sequences may be non-orthologous. We also evaluated enniatin, fumonisin and moniliformin mycotoxin production in vitro within a phylogenetic framework....

  9. Comparative analysis of chimeric ZFP-, TALE- and Cas9-piggyBac transposases for integration into a single locus in human cells.

    Science.gov (United States)

    Luo, Wentian; Galvan, Daniel L; Woodard, Lauren E; Dorset, Dan; Levy, Shawn; Wilson, Matthew H

    2017-08-21

    Integrating DNA delivery systems hold promise for many applications including treatment of diseases; however, targeted integration is needed for improved safety. The piggyBac (PB) transposon system is a highly active non-viral gene delivery system capable of integrating defined DNA segments into host chromosomes without requiring homologous recombination. We systematically compared four different engineered zinc finger proteins (ZFP), four transcription activator-like effector proteins (TALE), CRISPR associated protein 9 (SpCas9) and the catalytically inactive dSpCas9 protein fused to the amino-terminus of the transposase enzyme designed to target the hypoxanthine phosphoribosyltransferase (HPRT) gene located on human chromosome X. Chimeric transposases were evaluated for expression, transposition activity, chromatin immunoprecipitation at the target loci, and targeted knockout of the HPRT gene in human cells. One ZFP-PB and one TALE-PB chimera demonstrated notable HPRT gene targeting. In contrast, Cas9/dCas9-PB chimeras did not result in gene targeting. Instead, the HPRT locus appeared to be protected from transposon integration. Supplied separately, PB permitted highly efficient isolation of Cas9-mediated knockout of HPRT, with zero transposon integrations in HPRT by deep sequencing. In summary, these tools may allow isolation of 'targeted-only' cells, be utilized to protect a genomic locus from transposon integration, and enrich for Cas9-mutated cells. Published by Oxford University Press on behalf of Nucleic Acids Research 2017.

  10. The Locus Preservation Hypothesis: Shared Linguistic Profiles across Developmental Disorders and the Resilient Part of the Human Language Faculty

    Directory of Open Access Journals (Sweden)

    Evelina Leivada

    2017-10-01

    Full Text Available Grammatical markers are not uniformly impaired across speakers of different languages, even when speakers share a diagnosis and the marker in question is grammaticalized in a similar way in these languages. The aim of this work is to demarcate, from a cross-linguistic perspective, the linguistic phenotype of three genetically heterogeneous developmental disorders: specific language impairment, Down syndrome, and autism spectrum disorder. After a systematic review of linguistic profiles targeting mainly English-, Greek-, Catalan-, and Spanish-speaking populations with developmental disorders (n = 880, shared loci of impairment are identified and certain domains of grammar are shown to be more vulnerable than others. The distribution of impaired loci is captured by the Locus Preservation Hypothesis which suggests that specific parts of the language faculty are immune to impairment across developmental disorders. Through the Locus Preservation Hypothesis, a classical chicken and egg question can be addressed: Do poor conceptual resources and memory limitations result in an atypical grammar or does a grammatical breakdown lead to conceptual and memory limitations? Overall, certain morphological markers reveal themselves as highly susceptible to impairment, while syntactic operations are preserved, granting support to the first scenario. The origin of resilient syntax is explained from a phylogenetic perspective in connection to the “syntax-before-phonology” hypothesis.

  11. Association Between Genetic Polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT Genes and Radiosensitivity in Breast Cancer Patients

    International Nuclear Information System (INIS)

    Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca; Sani, Cristina; Biti, Giampaolo; Livi, Lorenzo; Barletta, Emanuela; Costantini, Adele Seniori; Gorini, Giuseppe

    2011-01-01

    Purpose: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Methods and Materials: Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR = 53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR = 38.26; 95% CI, 1.19-1232.52). Conclusions: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be

  12. MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions.

    Science.gov (United States)

    Park, Sang Mee; Park, Hae Ryoun; Lee, Ji Hye

    2017-02-01

    Proper synaptic function in neural circuits requires precise pairings between correct pre- and post-synaptic partners. Errors in this process may underlie development of neuropsychiatric disorders, such as autism spectrum disorder (ASD). Development of ASD can be influenced by genetic factors, including copy number variations (CNVs). In this study, we focused on a CNV occurring at the 16p11.2 locus in the human genome and investigated potential defects in synaptic connectivity caused by reduced activities of genes located in this region at Drosophila larval neuromuscular junctions, a well-established model synapse with stereotypic synaptic structures. A mutation of rolled , a Drosophila homolog of human mitogen-activated protein kinase 3 ( MAPK3 ) at the 16p11.2 locus, caused ectopic innervation of axonal branches and their abnormal defasciculation. The specificity of these phenotypes was confirmed by expression of wild-type rolled in the mutant background. Albeit to a lesser extent, we also observed ectopic innervation patterns in mutants defective in Cdk2, Gα q , and Gp93, all of which were expected to interact with Rolled MAPK3. A further genetic analysis in double heterozygous combinations revealed a synergistic interaction between rolled and Gp93 . In addition, results from RT-qPCR analyses indicated consistently reduced rolled mRNA levels in Cdk2 , Gα q , and Gp93 mutants. Taken together, these data suggest a central role of MAPK3 in regulating the precise targeting of presynaptic axons to proper postsynaptic targets, a critical step that may be altered significantly in ASD.

  13. Loss of a putative tumor suppressor locus after gamma-ray-induced neoplastic transformation of HeLa x Skin fibroblast human cell hybrids

    International Nuclear Information System (INIS)

    Mendonca, M.S.; Redpath, J.L.; Fasching, C.L.

    1995-01-01

    The nontumorigenic HeLa x skin fibroblast hybrid cell line, CGL1, can be induced to re-express HeLa tumor-associated cell surface antigen, p75-IAP (intestinal alkaline phosphatase), with resulting neoplastic transformation, by exposure to γ radiation. This has allowed the human hybrid system to be developed into a quantitative in vitro model for radiation-induced neoplastic transformation of human cells. Recently, several γ-ray-induced IAP-expression mutants (GIMs) of the nontumorigenic HeLa x skin fibroblast hybrid CGL1 were isolated and all were tumorigenic when injected subcutaneously into nude mice. Control cell lines which were negative for p75-IAP (CONs) were also isolated from irradiated populations, and none were found to be tumorigenic. We have now begun to investigate the molecular basis of radiation-induced neoplastic transformation in this system by studying the potential genetic linkage between p75/IAP expression, tumorigenicity and damage to a putative tumor suppressor locus on fibroblast chromosome 11. Previous analysis of rare spontaneous segregants has indicated that this locus is involved in the regulation of tumorigenicity and in the expression of the HeLa tumor-associated cell surface marker intestinal alkaline phosphatase (p75-IAP) in this system. Therefore, analysis by restriction fragment length polymorphism and chromosome painting have been performed for chromosome 11, and for chromosome 13 as a control, for the p75/IAP-positive GIM and p75/IAP-negative CON cell lines. We report that in five of eight of the GIMs large-scale damage to the fibroblast chromosome 11's is evident (four GIMs have lost one complete copy of a fibroblast chromosome 11 heavily damaged). None of the CONs, however (0/5), have lost a complete copy of either fibroblast chromosome 11. No large-scale damage to the control chromosome 13's was detected in the GIMs or CONs. 49 refs., 3 figs., 2 tabs

  14. Genotyping of TRIM5 locus in northern pig-tailed macaques (Macaca leonina, a primate species susceptible to Human Immunodeficiency Virus type 1 infection

    Directory of Open Access Journals (Sweden)

    Jiang Xue-Long

    2009-06-01

    Full Text Available Abstract Background The pig-tailed macaques are the only Old World monkeys known to be susceptible to human immunodeficiency virus type 1 (HIV-1 infection. We have previously reported that the TRIM5-Cyclophilin A (TRIMCyp fusion in pig-tailed macaques (Macaca nemestrina is dysfunctional in restricting HIV-1, which may explain why pig-tailed macaques are susceptible to HIV-1 infection. Similar results have also been reported by other groups. However, according to the current primate taxonomy, the previously reported M. nemestrina are further classified into three species, which all belong to the Macaca spp. This calls for the need to look into the previous studies in more details. Results The local species Northern pig-tailed macaque (M. leonina was analyzed for the correlation of TRIM5 structure and HIV-1 infection. Eleven M. leonina animals were analyzed, and all of them were found to possess TRIM5-CypA fusion at the TRIM5 locus. The transcripts encoding the dysfunctional TRIM5-CypA should result from the G-to-T mutation in the 3'-splicing site of intron 6. Polymorphism in the putative TRIMCyp recognition domain was observed. The peripheral blood mononuclear cells (PBMCs of M. leonina were susceptible to HIV-1 infection. Consistent with the previous results, expression of the M. leonina TRIMCyp in HeLa-T4 cells rendered the cells resistant to HIV-2ROD but not to SIVmac239 infection. Conclusion The susceptibility of M. leonina to HIV-1 infection is due to the dysfunctional TRIM5-CypA fusion in the TRIM5 locus. This finding should broaden our perspective in developing better HIV/AIDS non-human primate animal models.

  15. An Undergraduate Laboratory Experiment for Upper-Level Forensic Science, Biochemistry, or Molecular Biology Courses: Human DNA Amplification Using STR Single Locus Primers by Real-Time PCR with SYBR Green Detection

    Science.gov (United States)

    Elkins, Kelly M.; Kadunc, Raelynn E.

    2012-01-01

    In this laboratory experiment, real-time polymerase chain reaction (real-time PCR) was conducted using published human TPOX single-locus DNA primers for validation and various student-designed short tandem repeat (STR) primers for Combined DNA Index System (CODIS) loci. SYBR Green was used to detect the amplification of the expected amplicons. The…

  16. Characterization of the human oncogene SCL/TAL1 interrupting locus (Stil) mediated Sonic hedgehog (Shh) signaling transduction in proliferating mammalian dopaminergic neurons

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Lei [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Department of Physiology, Nankai University School of Medicine, Tianjin 300071 (China); Carr, Aprell L. [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556 (United States); Li, Ping; Lee, Jessica; McGregor, Mary [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Li, Lei, E-mail: Li.78@nd.edu [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556 (United States)

    2014-07-11

    Highlights: • Stil is a human oncogene that is conserved in vertebrate species. • Stil functions in the Shh pathway in mammalian cells. • The expression of Stil is required for mammalian dopaminergic cell proliferation. - Abstract: The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in all vertebrate species. In humans, the expression of Stil is involved in cancer cell survival, apoptosis and proliferation. In this research, we investigated the roles of Stil expression in cell proliferation of mammalian dopaminergic (DA) PC12 cells. Stil functions through the Sonic hedgehog (Shh) signal transduction pathway. Co-immunoprecipitation tests revealed that STIL interacts with Shh downstream components, which include SUFU and GLI1. By examining the expression of Stil, Gli1, CyclinD2 (cell-cycle marker) and PCNA (proliferating cell nuclear antigen), we found that up-regulation of Stil expression (transfection with overexpression plasmids) increased Shh signaling transduction and PC12 cell proliferation, whereas down-regulation of Stil expression (by shRNA) inhibited Shh signaling transduction, and thereby decreased PC12 cell proliferation. Transient transfection of PC12 cells with Stil knockdown or overexpression plasmids did not affect PC12 cell neural differentiation, further indicating the specific roles of Stil in cell proliferation. The results from this research suggest that Stil may serve as a bio-marker for neurological diseases involved in DA neurons, such as Parkinson’s disease.

  17. Locus of Control and Obesity

    Directory of Open Access Journals (Sweden)

    Florence eNeymotin

    2014-10-01

    Full Text Available In the developed world, the hazards associated with obesity have largely outstripped the risk of starvation. Obesity remains a difficult public health issue to address, due in large part to the many disciplines involved. A full understanding requires knowledge in the fields of genetics, endocrinology, psychology, sociology, economics, and public policy – among others. In this short review, which serves as an introduction to the Frontiers in Endocrinology research topic, we address one cross-disciplinary relationship: the interaction between the hunger/satiation neural circuitry, an individual’s perceived locus of control, and the risk for obesity. Mammals have evolved a complex system for modulating energy intake. Overlaid on this, in humans, there exists a wide variation in perceived locus of control – that is, the extent to which an individual believes to be in charge of the events that affect them. Whether one has primarily an internal or external locus of control itself affects, and is affected by, external and physiological factors and has been correlated with the risk for obesity. Thus, the path from hunger and satiation to an individual’s actual behavior may often be moderated by psychological factors, included among which is locus of control.

  18. Locus of control and obesity.

    Science.gov (United States)

    Neymotin, Florence; Nemzer, Louis R

    2014-01-01

    In the developed world, the hazards associated with obesity have largely outstripped the risk of starvation. Obesity remains a difficult public health issue to address, due in large part to the many disciplines involved. A full understanding requires knowledge in the fields of genetics, endocrinology, psychology, sociology, economics, and public policy - among others. In this short review, which serves as an introduction to the Frontiers in Endocrinology research topic, we address one cross-disciplinary relationship: the interaction between the hunger/satiation neural circuitry, an individual's perceived locus of control, and the risk for obesity. Mammals have evolved a complex system for modulating energy intake. Overlaid on this, in humans, there exists a wide variation in "perceived locus of control" - that is, the extent to which an individual believes to be in charge of the events that affect them. Whether one has primarily an internal or external locus of control itself affects, and is affected by, external and physiological factors and has been correlated with the risk for obesity. Thus, the path from hunger and satiation to an individual's actual behavior may often be moderated by psychological factors, included among which is locus of control.

  19. Multidimensional human capital formation in a developing country: Health, cognition and locus of control in the Philippines.

    Science.gov (United States)

    Villa, Kira M

    2017-11-01

    Economic success depends on multiple human capital stocks whose production is interrelated and occurs over many life stages. Yet, much empirical work fails to account for human capital's multidimensional nature and limits its focus to specific childhood stages. Using longitudinal data from the Philippines, I estimate a model of multidimensional human capital formation from birth through adulthood where health, cognitive, and noncognitive dimensions are jointly produced. I examine during which developmental stages parental investment is most influential and address the endogeneity of investment using a policy function where investment depends on child characteristics, exogenous conditions at birth and local prices. Findings imply that not only will early human capital disparities persist into adulthood without early remediation but also that cognitive gains yielded from early remediation will be lost without complementary investment in adolescence. Findings further suggest that interventions will be undervalued if their multidimensional effects are not accounted for. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Differential sequence diversity at merozoite surface protein-1 locus of Plasmodium knowlesi from humans and macaques in Thailand.

    Science.gov (United States)

    Putaporntip, Chaturong; Thongaree, Siriporn; Jongwutiwes, Somchai

    2013-08-01

    To determine the genetic diversity and potential transmission routes of Plasmodium knowlesi, we analyzed the complete nucleotide sequence of the gene encoding the merozoite surface protein-1 of this simian malaria (Pkmsp-1), an asexual blood-stage vaccine candidate, from naturally infected humans and macaques in Thailand. Analysis of Pkmsp-1 sequences from humans (n=12) and monkeys (n=12) reveals five conserved and four variable domains. Most nucleotide substitutions in conserved domains were dimorphic whereas three of four variable domains contained complex repeats with extensive sequence and size variation. Besides purifying selection in conserved domains, evidence of intragenic recombination scattering across Pkmsp-1 was detected. The number of haplotypes, haplotype diversity, nucleotide diversity and recombination sites of human-derived sequences exceeded that of monkey-derived sequences. Phylogenetic networks based on concatenated conserved sequences of Pkmsp-1 displayed a character pattern that could have arisen from sampling process or the presence of two independent routes of P. knowlesi transmission, i.e. from macaques to human and from human to humans in Thailand. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus.

    Directory of Open Access Journals (Sweden)

    Chul-Woo Pyo

    Full Text Available The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ~6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ~1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region.

  2. Mouse to human comparative genetics reveals a novel immunoglobulin E-controlling locus on Hsa8q12

    Czech Academy of Sciences Publication Activity Database

    Gusareva, Elena; Havelková, Helena; Blažková, Hana; Kosařová, Marcela; Kučera, P.; Král, V.; Salyakina, D.; Mulller-Myhsok, b.; Lipoldová, Marie

    2009-01-01

    Roč. 61, č. 1 (2009), s. 15-25 ISSN 0093-7711 R&D Projects: GA ČR GA310/06/1745; GA MŠk(CZ) LC06009 Institutional research plan: CEZ:AV0Z50520514 Keywords : atopy * specific IgE * genetic loci * mouse-human homology * Czech population * 8q12 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.988, year: 2009

  3. A high frequency MspI RFLP at the human vitamin D binding protein (hDBP) locus

    Energy Technology Data Exchange (ETDEWEB)

    Ray, K; Cooke, N E [Univ. of Pennsylvania, Philadelphia (USA)

    1988-07-25

    A nearly full-length cDNA encoding the human vitamin D binding protein (hDBP), also known as Gc-globulin, was isolated from a human liver cDNA expression library. This 1.73 kb cDNA was digested with EcoRI and the 5{prime}, 140 bp fragment of the cDNA, subcloned into plasmid SP65 (phDBP140), was used as probe. MspI identifies a two allele polymorphism with either a band at 12 kb or a band at 5 kb. The frequency was estimated from a study of 24 unrelated North American Caucasians. The hDBP gene has been localized to chromosome 4 using a cDNA probe and a panel of rodent X human somatic cell hybrids. It was sublocalized to 4q11-q13 by in situ hybridization. Co-dominant autosomal segregation of the polymorphic alleles has been observed in two informative families (20 individuals). With overexposure of the autoradiograph two faint variant bands are seen at 17 kb and 13.5 kb which appear to cosegregate with the 12 kb band and the 5 kb band respectively.

  4. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

    DEFF Research Database (Denmark)

    Deelen, Joris; Beekman, Marian; Uh, Hae-Won

    2014-01-01

    descent (≥ 85 years) and 16 121 younger controls (controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected...... by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103......, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less...

  5. Functional characterization of rs2229094 (T>C polymorphism in the tumor necrosis factor locus and lymphotoxin alpha expression in human retina: the Retina 4 project

    Directory of Open Access Journals (Sweden)

    Pastor-Idoate S

    2017-05-01

    Full Text Available Salvador Pastor-Idoate,1,2 Irene Rodríguez-Hernández,2,3 Jimena Rojas,1 Lucia Gonzalez-Buendia,1 Santiago Delgado-Tirado,1,4 Jose Carlos López,1 Rogelio González-Sarmiento,2,3 Jose C Pastor1,4 1IOBA Eye Institute, University of Valladolid, Valladolid, 2Molecular Medicine Unit, Department of Medicine, 3Molecular and Cellular Cancer Biology Institute, High Council of Scientific Research, Biomedical Research Institute of Salamanca, University of Salamanca, Salamanca, 4Department of Ophthalmology, Hospital Clínico Universitario, Valladolid, Spain Purpose: The objective of this study is to determine the expression and localization of lymphotoxin alpha (LTA in human retinas and the functionality of one of its polymorphisms rs2229094 (C13R (T>C, previously associated with proliferative vitreoretinopathy (PVR development.Materials and methods: Total RNA from three healthy human retinas were extracted and subjected to reverse transcription-polymerase chain reaction (RT-PCR analysis, using flanking primers of LTA cDNA. In addition, three human eyes with retinal detachment (RD and three healthy control eyes were subjected to immunohistochemistry (IHC with a specific antibody against LTA. The functionality of T and C alleles was assessed by using pCEFL-Flag expression vector and transient transfection assays in COS-1 cell line. In addition, expression analysis by RT-PCR, Western blot and subcellular localization of both alleles and by immunofluorescence assay was performed.Results: RT-PCR analysis revealed no significant levels of messenger RNA (mRNA LTA in healthy human retinas. Sequential IHC staining showed differences between healthy human and RD retinas. No differences in mRNA and protein expression levels and in subcellular localization between both alleles were found. Both alleles were located in the cytoplasm of COS-1 cells.Conclusion: Although results suggest lack of functionality, the differences found in IHC study and its strong association

  6. Image simulation using LOCUS

    International Nuclear Information System (INIS)

    Strachan, J.D.; Roberts, J.A.

    1989-09-01

    The LOCUS data base program has been used to simulate images and to solve simple equations. This has been accomplished by making each record (which normally would represent a data entry)represent sequenced or random number pairs

  7. Mapping the end points of large deletions affecting the hprt locus in human peripheral blood cells and cell lines

    International Nuclear Information System (INIS)

    Nelson, S.L.; Grosovsky, A.J.; Jones, I.M.; Burkhart-Schultz, K.; Fuscoe, J.C.

    1995-01-01

    We have examined the extent of of HPRT - total gene deletions in three mutant collections: spontaneous and X-ray-induced deletions in TK6 human B lymphoblasts, and HPRT - deletions arising in vivo in T cells. A set of 13 Xq26 STS markers surrounding hprt and spanning approximately 3.3 Mb was used. Each marker used was observed to be missing in at least one of the hprt deletion mutants analyzed. The largest deletion observed encompassed at least 3 Mb. Nine deletions extended outside of the mapped region in the centromeric direction (>1.7 Mb). In contrast, only two telomeric deletions extended to marker 342R (1.26 Mb), and both exhibited slowed or limited cell growth. These data suggest the existence of a gene, within the vicinity of 342R, which establishes the telomeric limit of recoverable deletions. Most (25/41) X-ray-induced total gene deletion mutants exhibited marker loss, but only 1/8 of the spontaneous deletions encompassed any Xq26 markers (P = 0.0187). Furthermore, nearly half (3/8) of the spontaneous 3' total deletion breakpoints were within 14 kb of the hprt coding sequence. In contrast, 40/41 X-ray-induced HPRT - total deletions extended beyond this point (P = 0.011). Although the overall representation of total gene deletions in the in vivo spectrum is low, 4/5 encompass Xq26 markers flanking hprt. This pattern differs significantly from spontaneous HPRT - large deletions occurring in vitro (P = 0.032) but resembles the spectrum of X-ray-induced deletions. 24 refs., 6 figs., 1 tab

  8. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G locus in subjects to recurrent miscarriage

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    Nazila Alizadeh

    2016-07-01

    Full Text Available Background: Human leukocyte antigen-G (HLA-G is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR. Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele.

  9. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage

    Science.gov (United States)

    Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

    2016-01-01

    Background: Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele. PMID:27525330

  10. Improving resolution of public health surveillance for human Salmonella enterica serovar Typhimurium infection: 3 years of prospective multiple-locus variable-number tandem-repeat analysis (MLVA

    Directory of Open Access Journals (Sweden)

    Sintchenko Vitali

    2012-03-01

    Full Text Available Abstract Background Prospective typing of Salmonella enterica serovar Typhimurium (STM by multiple-locus variable-number tandem-repeat analysis (MLVA can assist in identifying clusters of STM cases that might otherwise have gone unrecognised, as well as sources of sporadic and outbreak cases. This paper describes the dynamics of human STM infection in a prospective study of STM MLVA typing for public health surveillance. Methods During a three-year period between August 2007 and September 2010 all confirmed STM isolates were fingerprinted using MLVA as part of the New South Wales (NSW state public health surveillance program. Results A total of 4,920 STM isolates were typed and a subset of 4,377 human isolates was included in the analysis. The STM spectrum was dominated by a small number of phage types, including DT170 (44.6% of all isolates, DT135 (13.9%, DT9 (10.8%, DT44 (4.5% and DT126 (4.5%. There was a difference in the discriminatory power of MLVA types within endemic phage types: Simpson's index of diversity ranged from 0.109 and 0.113 for DTs 9 and 135 to 0.172 and 0.269 for DTs 170 and 44, respectively. 66 distinct STM clusters were observed ranging in size from 5 to 180 cases and in duration from 4 weeks to 25 weeks. 43 clusters had novel MLVA types and 23 represented recurrences of previously recorded MLVA types. The diversity of the STM population remained relatively constant over time. The gradual increase in the number of STM cases during the study was not related to significant changes in the number of clusters or their size. 667 different MLVA types or patterns were observed. Conclusions Prospective MLVA typing of STM allows the detection of community outbreaks and demonstrates the sustained level of STM diversity that accompanies the increasing incidence of human STM infections. The monitoring of novel and persistent MLVA types offers a new benchmark for STM surveillance. A part of this study was presented at the MEEGID

  11. Distribution and factors associated with Salmonella enterica genotypes in a diverse population of humans and animals in Qatar using multi-locus sequence typing (MLST).

    Science.gov (United States)

    Chang, Yu C; Scaria, Joy; Ibraham, Mariamma; Doiphode, Sanjay; Chang, Yung-Fu; Sultan, Ali; Mohammed, Hussni O

    2016-01-01

    Salmonella enterica is one of the most commonly reported causes of bacterial foodborne illness around the world. Understanding the sources of this pathogen and the associated factors that exacerbate its risk to humans will help in developing risk mitigation strategies. The genetic relatedness among Salmonella isolates recovered from human gastroenteritis cases and food animals in Qatar were investigated in the hope of shedding light on these sources, their possible transmission routes, and any associated factors. A repeat cross-sectional study was conducted in which the samples and associated data were collected from both populations (gastroenteritis cases and animals). Salmonella isolates were initially analyzed using multi-locus sequence typing (MLST) to investigate the genetic diversity and clonality. The relatedness among the isolates was assessed using the minimum spanning tree (MST). Twenty-seven different sequence types (STs) were identified in this study; among them, seven were novel, including ST1695, ST1696, ST1697, ST1698, ST1699, ST1702, and ST1703. The pattern of overall ST distribution was diverse; in particular, it was revealed that ST11 and ST19 were the most common sequence types, presenting 29.5% and 11.5% within the whole population. In addition, 20 eBurst Groups (eBGs) were identified in our data, which indicates that ST11 and ST19 belonged to eBG4 and eBG1, respectively. In addition, the potential association between the putative risk factors and eBGs were evaluated. There was no significant clustering of these eBGs by season; however, a significant association was identified in terms of nationality in that Qataris were six times more likely to present with eBG1 compared to non-Qataris. In the MST analysis, four major clusters were presented, namely, ST11, ST19, ST16, and ST31. The linkages between the clusters alluded to a possible transmission route. The results of the study have provided insight into the ST distributions of S. enterica and

  12. Use of multiple-locus variable-number of tandem repeats analysis (MLVA) to investigate genetic diversity of Salmonella enterica subsp. enterica serovar Typhimurium isolates from human, food, and veterinary sources

    DEFF Research Database (Denmark)

    Mateva, Gergana; Pedersen, Karl; Sørensen, Gitte

    2017-01-01

    -locus variable-number of tandem repeats analysis (MLVA) and compared results with antimicrobial resistance (AMR) determinations for 100 S. Typhimurium strains isolated in Bulgaria during 2008-2012 (50 veterinary/food and 50 human isolates). Results showed that isolates were divided into 80 and 34 groups using......). No clustering of isolates related to susceptibility/resistance to antimicrobials, source of isolation, or year of isolation was observed. Some MLVA types were found in both human and veterinary/food isolates, indicating a possible route of transmission. A majority (83%) of the isolates were found...

  13. Endogenous Locus Reporter Assays.

    Science.gov (United States)

    Liu, Yaping; Hermes, Jeffrey; Li, Jing; Tudor, Matthew

    2018-01-01

    Reporter gene assays are widely used in high-throughput screening (HTS) to identify compounds that modulate gene expression. Traditionally a reporter gene assay is built by cloning an endogenous promoter sequence or synthetic response elements in the regulatory region of a reporter gene to monitor transcriptional activity of a specific biological process (exogenous reporter assay). In contrast, an endogenous locus reporter has a reporter gene inserted in the endogenous gene locus that allows the reporter gene to be expressed under the control of the same regulatory elements as the endogenous gene, thus more accurately reflecting the changes seen in the regulation of the actual gene. In this chapter, we introduce some of the considerations behind building a reporter gene assay for high-throughput compound screening and describe the methods we have utilized to establish 1536-well format endogenous locus reporter and exogenous reporter assays for the screening of compounds that modulate Myc pathway activity.

  14. Natural breaking of the maternal silence at the mouse and human imprinted Prader-Willi locus: A whisper with functional consequences.

    Science.gov (United States)

    Matarazzo, Valery; Muscatelli, Françoise

    2013-01-01

    Genomic imprinting is a normal process of epigenetic regulation leading some autosomal genes to be expressed from one parental allele only, the other parental allele being silenced. The reasons why this mechanism has been selected throughout evolution are not clear; however, expression dosage is critical for imprinted genes. There is a paradox between the fact that genomic imprinting is a robust mechanism controlling the expression of specific genes and the fact that this mechanism is based on epigenetic regulation that, per se, should present some flexibility. The robustness has been well studied, revealing the epigenetic modifications at the imprinted locus, but the flexibility has been poorly investigated.   Prader-Willi syndrome is the best-studied disease involving imprinted genes caused by the absence of expression of paternally inherited alleles of genes located in the human 15q11-q13 region. Until now, the silencing of the maternally inherited alleles was like a dogma. Rieusset et al. showed that in absence of the paternal Ndn allele, in Ndn +m/-p mice, the maternal Ndn allele is expressed at an extremely low level with a high degree of non-genetic heterogeneity. In about 50% of these mutant mice, this stochastic expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. Furthermore, using several mouse models, they reveal a competition between non-imprinted Ndn promoters, which results in monoallelic (paternal or maternal) Ndn expression, suggesting that Ndn monoallelic expression occurs in the absence of imprinting regulation. Importantly, specific expression of the maternal NDN allele is also detected in post-mortem brain samples of PWS individuals. Here, similar expression of the Magel2 maternal allele is reported in Magel2 +m/-p mice, suggesting that this loss of imprinting can be extended to other PWS genes. These data reveal an unexpected epigenetic flexibility of PWS

  15. Locus of control in relation to flow

    Directory of Open Access Journals (Sweden)

    Celeste M Taylor

    2006-04-01

    Full Text Available The principal objective of the study was to examine the relationship between locus of control and optimal experience (flow in carrying out work and/or study activities. Two questionnaires measuring the aforementioned constructs were administered to a group of first and second-year Human Resource Management students (n=168 between the ages of 16 and 30. The results suggest that more frequent experience of flow is positively correlated with Autonomy and Internal Locus of Control. Limitations, lines of future research, implications and further contributions are discussed.

  16. Characterization of a human X-linked gene from the DXS732E locus in the candidate region for the anhidrotic ectodermal dysplasia (EDA) gene (Xq13.1)

    Energy Technology Data Exchange (ETDEWEB)

    Gault, J.; Zonana, J. [Oregon Health Sciences Univ., Portland, OR (United States); Zeltinger, J. [Univ. of Washington, Seattle, WA (United States)] [and others

    1994-09-01

    A conserved mouse genomic clone was used to identify a homologous human genomic clone (the DXS732E locus), which was subsequently employed to isolate cDNAs from a human fetal brain library. Nine unique overlapping cDNAs were isolated, and sequences analysis of 3.9 kb identified a putative 1 kb ORF. GRAIL analysis of the sequence supported the hypothesis that the putative ORF was coding sequence, and Prosite analysis of the putative ORF identified potential glycosylation and phosphorylation sites. The 5{prime} end of the gene maps within a CpG island, and comparison of cDNA sequences indicate the gene is alternatively spliced at its 3{prime} end. Northern analysis and RT-PCR indicate that two different sized messages appear to be expressed with the gene expressed in human fetal kidney, intestine, brain, and muscle. The gene is expressed in 77 day human skin, a time when hair follicle formation occurs. Anhidrotic ectodermal dysplasia (EDA) results in the abnormal morphogenesis of hair, teeth and eccrine sweat glands. A positional cloning strategy towards cloning the EDA gene had been used, and deletion and X-autosome translocation patients have been useful in further delimiting the EDA region. The present gene at the DXS732E locus is partially deleted in one EDA patient who does not have other apparent abnormalities. No rearrangements of the gene have been detected in two female X-autosome translocation EDA patients, nor in four additional male patients with submicroscopic molecular deletions.

  17. Genetic recombination at the human RH locus: A family study of the red-cell Evans phenotype reveals a transfer of exons 2-6 from the RHD to the RHCE gene

    Energy Technology Data Exchange (ETDEWEB)

    Huang, C.H.; Chen, Y.; Reid, M. [Lindsley F. Kimball Research Inst., New York, NY (United States); Ghosh, S.

    1996-10-01

    The human RH locus appears to consist of two structural genes, D and CE, which map on the short arm p34-36 of chromosome 1 and specify a most complex system of blood-group genetic polymorphisms. Here we describe a family study of the Evans (also known as {open_quotes}D..{open_quotes}) phenotype, a codominant trait associated with both qualitative and quantitative changes in D-antigen expression. A cataract-causing mutation was also inherited in this family and was apparently cotransmitted with Evans, suggesting a chromosomal linkage of these two otherwise unrelated traits. Southern blot analysis and allele-specific PCR showed the linkage of Evans with a SphI RFLP marker and the presence of a hybrid gene in the RH locus. To delineate the pattern of gene expression, the composition and structure of Rh-polypeptide transcripts were characterized by reverse transcriptase-PCR and nucleotide sequencing. This resulted in the identification of a novel Rh transcript expressed only in the Evans-positive erythroid cells. Sequence analysis showed that the transcript maintained a normal open reading frame but occurred as a CE-D-CE composite in which exons 2-6 of the CE gene were replaced by the homologous counterpart of the D gene. This hybrid gene was predicted to encode a CE-D-CE fusion protein whose surface expression correlates with the Evans phenotype. The mode and consequence of such a recombination event suggest the occurrence, in the RH locus, of a segmental DNA transfer via the mechanism of gene conversion. 31 refs., 6 figs., 1 tab.

  18. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study.

    Directory of Open Access Journals (Sweden)

    Natasha Z R Steele

    2017-03-01

    Full Text Available Alzheimer disease (AD is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls from the San Francisco-based University of California, San Francisco (UCSF Memory and Aging Center (collected between 1999-2015 and 11,381 individuals (5,728 AD, 5,653 CN controls from the Alzheimer's Disease Genetics Consortium (ADGC, a National Institute on Aging (NIA-funded national data repository (reflecting samples collected between 1984-2012. We also examined cerebrospinal fluid (CSF biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37] in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE ɛ4. Separate

  19. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study.

    Science.gov (United States)

    Steele, Natasha Z R; Carr, Jessie S; Bonham, Luke W; Geier, Ethan G; Damotte, Vincent; Miller, Zachary A; Desikan, Rahul S; Boehme, Kevin L; Mukherjee, Shubhabrata; Crane, Paul K; Kauwe, John S K; Kramer, Joel H; Miller, Bruce L; Coppola, Giovanni; Hollenbach, Jill A; Huang, Yadong; Yokoyama, Jennifer S

    2017-03-01

    Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate

  20. Analysis of the ABCA4 genomic locus in Stargardt disease

    DEFF Research Database (Denmark)

    Zernant, Jana; Xie, Yajing Angela; Ayuso, Carmen

    2014-01-01

    excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD...... patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches....

  1. High-resolution mapping of the x-linked hypohidrotic ectodermal dysplasia (EDA) locus

    Energy Technology Data Exchange (ETDEWEB)

    Zonana, J.; Jones, M.; Litt, M.; Kramer, P.; Browne, D.; Becker, H.W. (Oregon Health Sciences Univ., Portland, OR (United States)); Brockdorff, N.; Rastan, S. (Medical Council Clinical Research Centre, Harrow (United Kingdom)); Davies, K.P.; Clarke, A. (Univ. of Wales College of Medicine, Cardiff (United Kingdom)) (and others)

    1992-11-01

    The X-linked hypohidrotic ectodermal dysplasia (EDA) locus has been previously localized to the subchromosomal region Xq11-q21.1. The authors have extended previous linkage studies and analyzed linkage between the EDA locus and 10 marker loci, including five new loci, in 41 families. Four of the marker loci showed no recombination with the EDA locus, and six other loci were also linked to the EDA locus with recombination fractions of .009-.075. Multipoint analysis gave support to the placement of the PGK1P1 locus proximal to the EDA locus and the DXS453 and PGK1 loci distal to EDA. Further ordering of the loci could be inferred from a human-rodent somatic cell hybrid derived from an affected female with EDA and an X;9 translocation and from studies of an affected male with EDA and a submicroscopic deletion. Three of the proximal marker loci, which showed no recombination with the EDA locus, when used in combination, were informative in 92% of females. The closely linked flanking polymorphic loci DXS339 and DXS453 had heterozygosites of 72% and 76%, respectively, and when used jointly, they were doubly informative in 52% of females. The human DXS732 locus was defined by a conserved mouse probe pcos169E/4 (DXCrc169 locus) that consegregates with the mouse tabby (Ta) locus, a potential homologue to the EDA locus. The absence of recombination between EDA and the DXSA732 locus lends support to the hypothesis that the DXCrc169 locus in the mouse and the DXS732 locus in humans may contain candidate sequences for the Ta and EDA genes, respectively. 36 refs., 1 fig., 5 tabs.

  2. Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-β and Tau Pathology in Alzheimer's Disease.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2015-01-01

    A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer's disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tau(HYP)) appears early in these neurons. In an attempt to find out if both heavy metals and tau(HYP) could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tau(HYP) using AT8 immunostaining. Heavy metals or tau(HYP) were usually seen in separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tau(HYP). Heavy metals therefore appear to occupy a mostly different population of LC neurons to those containing tau(HYP), indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-β deposition, and tau(HYP) in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-β and tau pathologies of AD.

  3. Detección de mutaciones de los genes hMLH1 y hMSH2 del sistema de reparación de malos apareamientos del ADN en familias colombianas sospechosas de cancer colorrectal no polipósico hereditario (síndrome de Lynch.

    Directory of Open Access Journals (Sweden)

    Andrea Gómez

    2005-09-01

    Full Text Available Introducción. El cáncer colorrectal es la segunda causa de morbilidad y mortalidad por cáncer en los países desarrollados. En Colombia es la quinta causa de muerte entre los diferentes cánceres. Cerca del 75% de éstos corresponde a cánceres esporádicos, alrededor del 25% son familiares, y son claramente hereditarios el 5%. De éstos, el más importantes es el cáncer colorrectal no polipósico hereditario o síndrome de Lynch. Objetivo. Analizar los dos genes más importantes involucrados en el síndrome de Lynch, el hMLH1 y el hMSH2. Materiales y métodos. En 17 familias colombianas que cumplían con los criterios de Ámsterdam II o las pautas de Bethesda, se analizaron por SSCP los 35 exones de estos dos genes y las variantes electroforéticas se secuenciaron. Resultados. Se detectaron 8 mutaciones de línea germinal en las familias analizadas, 7 en el gen hMLH1 y 1 en hMSH2, y se encontró una tasa de detección de mutaciones del 47%. Seis de las 8 mutaciones encontradas en este estudio han sido previamente reportadas en la literatura. Un cambio de una base en el sitio donador de empalme en el exón 9 del gen hMLH1 (G>A (dos familias, un cambio A>G en el codón 755 del exón 17, y un cambio G>A en el exón 18. Se detectaron dos nuevas mutaciones, una en el exón 17, un cambio C>T en el codón 640, y una deleción de TG en el codón 184 del exón 3 del gen hMSH2. También se detectó en dos familias un polimorfismo del intrón 13 del hMLH1. Conclusión. Este es el primer estudio realizado en Colombia que detecta mutaciones en el síndrome de Lynch y pretende establecer un programa integral de manejo y prevención.

  4. Homology Requirements for Efficient, Footprintless Gene Editing at the CFTR Locus in Human iPSCs with Helper-dependent Adenoviral Vectors

    Directory of Open Access Journals (Sweden)

    Donna J Palmer

    2016-01-01

    Full Text Available Helper-dependent adenoviral vectors mediate high efficiency gene editing in induced pluripotent stem cells without needing a designer nuclease thereby avoiding off-target cleavage. Because of their large cloning capacity of 37 kb, helper-dependent adenoviral vectors with long homology arms are used for gene editing. However, this makes vector construction and recombinant analysis difficult. Conversely, insufficient homology may compromise targeting efficiency. Thus, we investigated the effect of homology length on helper-dependent adenoviral vector targeting efficiency at the cystic fibrosis transmembrane conductance regulator locus in induced pluripotent stem cells and found a positive correlation. With 23.8 and 21.4 kb of homology, the frequencies of targeted recombinants were 50–64.6% after positive selection for vector integration, and 97.4–100% after negative selection against random integrations. With 14.8 kb, the frequencies were 26.9–57.1% after positive selection and 87.5–100% after negative selection. With 9.6 kb, the frequencies were 21.4 and 75% after positive and negative selection, respectively. With only 5.6 kb, the frequencies were 5.6–16.7% after positive selection and 50% after negative selection, but these were more than high enough for efficient identification and isolation of targeted clones. Furthermore, we demonstrate helper-dependent adenoviral vector-mediated footprintless correction of cystic fibrosis transmembrane conductance regulator mutations through piggyBac excision of the selectable marker. However, low frequencies (≤ 1 × 10−3 necessitated negative selection for piggyBac-excision product isolation.

  5. Knock-in fibroblasts and transgenic blastocysts for expression of human FGF2 in the bovine β-casein gene locus using CRISPR/Cas9 nuclease-mediated homologous recombination.

    Science.gov (United States)

    Jeong, Young-Hee; Kim, Yeong Ji; Kim, Eun Young; Kim, Se Eun; Kim, Jiwoo; Park, Min Jee; Lee, Hong-Gu; Park, Se Pill; Kang, Man-Jong

    2016-06-01

    Many transgenic domestic animals have been developed to produce therapeutic proteins in the mammary gland, and this approach is one of the most important methods for agricultural and biomedical applications. However, expression and secretion of a protein varies because transgenes are integrated at random sites in the genome. In addition, distal enhancers are very important for transcriptional gene regulation and tissue-specific gene expression. Development of a vector system regulated accurately in the genome is needed to improve production of therapeutic proteins. The objective of this study was to develop a knock-in system for expression of human fibroblast growth factor 2 (FGF2) in the bovine β-casein gene locus. The F2A sequence was fused to the human FGF2 gene and inserted into exon 3 of the β-casein gene. We detected expression of human FGF2 mRNA in the HC11 mouse mammary epithelial cells by RT-PCR and human FGF2 protein in the culture media using western blot analysis when the knock-in vector was introduced. We transfected the knock-in vector into bovine ear fibroblasts and produced knock-in fibroblasts using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Moreover, the CRISPR/Cas9 system was more efficient than conventional methods. In addition, we produced knock-in blastocysts by somatic cell nuclear transfer using the knock-in fibroblasts. Our knock-in fibroblasts may help to create cloned embryos for development of transgenic dairy cattle expressing human FGF2 protein in the mammary gland via the expression system of the bovine β-casein gene.

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

    Directory of Open Access Journals (Sweden)

    Deeti K. Shetty

    2016-03-01

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

  7. Mutation Frequency Dynamics in HPRT Locus in Culture-Adapted Human Embryonic Stem Cells and Induced Pluripotent Stem Cells Correspond to Their Differentiated Counterparts

    Czech Academy of Sciences Publication Activity Database

    Krutá, M.; Seneklová, M.; Raška, J.; Salykin, A.; Zerzánková, L.; Pešl, M.; Bártová, Eva; Franěk, Michal

    2014-01-01

    Roč. 23, č. 20 (2014), s. 2443-2454 ISSN 1547-3287 R&D Projects: GA ČR(CZ) GBP302/12/G157; GA MŠk(CZ) ED1.100/02/0123 Institutional support: RVO:68081707 Keywords : BASE EXCISION-REPAIR * HUMAN SOMATIC-CELLS * X-INACTIVATION Subject RIV: BO - Biophysics Impact factor: 3.727, year: 2014

  8. Characterization of the human laminin beta2 chain locus (LAMB2): linkage to a gene containing a nonprocessed, transcribed LAMB2-like pseudogene (LAMB2L) and to the gene encoding glutaminyl tRNA synthetase (QARS)

    DEFF Research Database (Denmark)

    Durkin, M E; Jäger, A C; Khurana, T S

    1999-01-01

    The laminin beta2 chain is an important constituent of certain kidney and muscle basement membranes. We have generated a detailed physical map of a 110-kb genomic DNA segment surrounding the human laminin beta2 chain gene (LAMB2) on chromosome 3p21.3-->p21.2, a region paralogous with the chromosome...... 7q22-->q31 region that contains the laminin beta1 chain gene locus (LAMB1). Several CpG islands and a novel polymorphic microsatellite marker (D3S4594) were identified. The 3' end of LAMB2 lies 16 kb from the 5' end of the glutaminyl tRNA synthetase gene (QARS). About 20 kb upstream of LAMB2 we...... found a gene encoding a transcribed, non-processed LAMB2-like pseudogene (LAMB2L). The sequence of 1.75 kb of genomic DNA at the 3' end of LAMB2L was similar to exons 8-12 of the laminin beta2 chain gene. The LAMB2L-LAMB2-QARS cluster lies telomeric to the gene encoding the laminin-binding protein...

  9. The Effect of Locus of Control on Message Acceptance and Recall.

    Science.gov (United States)

    Cole, Catherine A.; Singh, Surendra

    Locus of control is a personality trait that influences human behavior in many situations. Internal-external control reactions to a persuasive message and the recall of the message were examined in two studies. In the first study, 35 undergraduate students' locus of control was measured using Duttweiler's Internal Control Measure. On the basis of…

  10. Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles

    International Nuclear Information System (INIS)

    Rodriguez-Antona, Cristina; Sayi, Jane G.; Gustafsson, Lars L.; Bertilsson, Leif; Ingelman-Sundberg, Magnus

    2005-01-01

    The human cytochrome P450 3A (CYP3A) enzymes, which metabolize 50% of currently used therapeutic drugs, exhibit great interindividual differences in activity that have a major impact on drug treatment outcome, but hitherto no genetic background importantly contributing to this variation has been identified. In this study we show that CYP3A4 mRNA and hnRNA contents with a few exceptions vary in parallel in human liver, suggesting that mechanisms affecting CYP3A4 transcription, such as promoter polymorphisms, are relevant for interindividual differences in CYP3A4 expression. Tanzanian (n = 143) healthy volunteers were phenotyped using quinine as a CYP3A probe and the results were used for association studies with CYP3A4 genotypes. Carriers of CYP3A4*1B had a significantly lower activity than those with CYP3A4*1 whereas no differences were seen for five other SNPs investigated. Nuclear proteins from the B16A2 hepatoma cells were found to bind with less affinity to the CYP3A4*1B element around -392 bp as compared to CYP3A4*1. The data indicate the existence of a genetic CYP3A4 polymorphism with functional importance for interindividual differences in enzyme expression

  11. Generation and characterization of a human iPSC cell line expressing inducible Cas9 in the “safe harbor” AAVS1 locus

    Directory of Open Access Journals (Sweden)

    Julio Castaño

    2017-05-01

    Full Text Available We report the generation-characterization of a fetal liver (FL B-cell progenitor (BCP-derived human induced pluripotent stem cell (hiPSC line CRISPR/Cas9-edited to carry/express a single copy of doxycycline-inducible Cas9 gene in the “safe locus” AAVS1 (iCas9-FL-BCP-hiPSC. Gene-edited iPSCs remained pluripotent after CRISPR/Cas9 genome-edition. Correct genomic integration of a unique copy of Cas9 was confirmed by PCR and Southern blot. Cas9 was robustly and specifically expressed on doxycycline exposure. T7-endonuclease assay demonstrated that iCas9 induces robust gene-edition when gRNAs against hematopoietic transcription factors were tested. This iCas9-FL-BCP-hiPSC will facilitate gene-editing approaches for studies on developmental biology, drug screening and disease modeling.

  12. Purification, crystallization and preliminary X-ray diffraction analysis of the human mismatch repair protein MutSβ

    International Nuclear Information System (INIS)

    Tseng, Quincy; Orans, Jillian; Hast, Michael A.; Iyer, Ravi R.; Changela, Anita; Modrich, Paul L.; Beese, Lorena S.

    2011-01-01

    Human MutSβ is a 232 kDa heterodimer (MSH2–MSH3) involved in the lesion-recognition step of mismatch repair. Here, the overexpression, purification, biochemical characterization and cocrystallization of MutSβ with a duplex DNA substrate are reported. MutSβ is a eukaryotic mismatch repair protein that preferentially targets extrahelical unpaired nucleotides and shares partial functional redundancy with MutSα (MSH2–MSH6). Although mismatch recognition by MutSα has been shown to involve a conserved Phe-X-Glu motif, little is known about the lesion-binding mechanism of MutSβ. Combined MSH3/MSH6 deficiency triggers a strong predisposition to cancer in mice and defects in msh2 and msh6 account for roughly half of hereditary nonpolyposis colorectal cancer mutations. These three MutS homologs are also believed to play a role in trinucleotide repeat instability, which is a hallmark of many neurodegenerative disorders. The baculovirus overexpression and purification of recombinant human MutSβ and three truncation mutants are presented here. Binding assays with heteroduplex DNA were carried out for biochemical characterization. Crystallization and preliminary X-ray diffraction analysis of the protein bound to a heteroduplex DNA substrate are also reported

  13. Locus ceruleus neurons in people with autism contain no histochemically-detectable mercury.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2016-02-01

    Exposure to environmental mercury has been proposed to play a part in autism. Mercury is selectively taken up by the human locus ceruleus, a region of the brain that has been implicated in autism. We therefore looked for the presence of mercury in the locus ceruleus of people who had autism, using the histochemical technique of autometallography which can detect nanogram amounts of mercury in tissues. In addition, we sought evidence of damage to locus ceruleus neurons in autism by immunostaining for hyperphosphorylated tau. No mercury was found in any neurons of the locus ceruleus of 6 individuals with autism (5 male, 1 female, age range 16-48 years). Mercury was present in locus ceruleus neurons in 7 of 11 (64%) age-matched control individuals who did not have autism, which is significantly more than in individuals with autism. No increase in numbers of locus ceruleus neurons containing hyperphosphorylated tau was detected in people with autism. In conclusion, most people with autism have not been exposed early in life to quantities of mercury large enough to be found later in adult locus ceruleus neurons. Human locus ceruleus neurons are sensitive indicators of mercury exposure, and mercury appears to remain in these neurons indefinitely, so these findings do not support the hypothesis that mercury neurotoxicity plays a role in autism.

  14. The Ties that Bind (the Igh Locus).

    Science.gov (United States)

    Krangel, Michael S

    2016-05-01

    Immunoglobulin heavy-chain locus V(D)J recombination requires a 3D chromatin organization which permits widely distributed variable (V) gene segments to contact distant diversity (D) and joining (J) gene segments. A recent study has identified key nodes in the locus interactome, paving the way for new molecular insights into how the locus is configured for recombination. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Investigation of the 5q33.3 longevity locus and age-related phenotypes

    DEFF Research Database (Denmark)

    Nygaard, Marianne; Thinggaard, Mikael; Christensen, Kaare

    2017-01-01

    A large meta-analysis recently found the 5q33.3 locus to be associated with survival to ≥ 90 years and lower all-cause mortality, thus suggesting it as a third human longevity locus alongside APOE and FOXO3A. The 5q33.3 locus has previously been associated with blood pressure regulation and cardi......A large meta-analysis recently found the 5q33.3 locus to be associated with survival to ≥ 90 years and lower all-cause mortality, thus suggesting it as a third human longevity locus alongside APOE and FOXO3A. The 5q33.3 locus has previously been associated with blood pressure regulation...... and cardiovascular diseases in middle-aged individuals. However, part of the influence on mortality appears to be independent of cardiovascular phenotypes, and the role of the 5q33.3 locus in longevity and survival is therefore still partly unknown. We investigated the association between the longevity......-associated variant rs2149954 on chromosome 5q33.3 and age-related phenotypes in two cohorts of 1,588 and 1,271 long-lived individuals (mean ages 93.1 and 95.9 years, respectively) as well as in 700 middle-aged and 677 elderly individuals (mean ages 52.5 and 78.7 years). Altogether, nominally significant associations...

  16. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

    Science.gov (United States)

    Rorabaugh, Jacki M; Chalermpalanupap, Termpanit; Botz-Zapp, Christian A; Fu, Vanessa M; Lembeck, Natalie A; Cohen, Robert M; Weinshenker, David

    2017-11-01

    See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a

  17. Organization of the cpe locus in CPE-positive clostridium perfringens type C and D isolates.

    Directory of Open Access Journals (Sweden)

    Jihong Li

    2010-06-01

    Full Text Available Clostridium perfringens enterotoxin (encoded by the cpe gene contributes to several important human, and possibly veterinary, enteric diseases. The current study investigated whether cpe locus organization in type C or D isolates resembles one of the three (one chromosomal and two plasmid-borne cpe loci commonly found amongst type A isolates. Multiplex PCR assays capable of detecting sequences in those type A cpe loci failed to amplify products from cpe-positive type C and D isolates, indicating these isolates possess different cpe locus arrangements. Therefore, restriction fragments containing the cpe gene were cloned and sequenced from two type C isolates and one type D isolate. The obtained cpe locus sequences were then used to construct an overlapping PCR assay to assess cpe locus diversity amongst other cpe-positive type C and D isolates. All seven surveyed cpe-positive type C isolates had a plasmid-borne cpe locus partially resembling the cpe locus of type A isolates carrying a chromosomal cpe gene. In contrast, all eight type D isolates shared the same plasmid-borne cpe locus, which differed substantially from the cpe locus present in other C. perfringens by containing two copies of an ORF with 67% identity to a transposase gene (COG4644 found in Tn1546, but not previously associated with the cpe gene. These results identify greater diversity amongst cpe locus organization than previously appreciated, providing new insights into cpe locus evolution. Finally, evidence for cpe gene mobilization was found for both type C and D isolates, which could explain their cpe plasmid diversity.

  18. A novel locus for dilated cardiomyopathy maps to canine chromosome 8.

    Science.gov (United States)

    Werner, Petra; Raducha, Michael G; Prociuk, Ulana; Sleeper, Meg M; Van Winkle, Thomas J; Henthorn, Paula S

    2008-06-01

    Dilated cardiomyopathy (DCM), the most common form of cardiomyopathy, often leads to heart failure and sudden death. While a substantial proportion of DCMs are inherited, mutations responsible for the majority of DCMs remain unidentified. A genome-wide linkage study was performed to identify the locus responsible for an autosomal recessive inherited form of juvenile DCM (JDCM) in Portuguese water dogs using 16 families segregating the disease. Results link the JDCM locus to canine chromosome 8 with two-point and multipoint lod scores of 10.8 and 14, respectively. The locus maps to a 3.9-Mb region, with complete syntenic homology to human chromosome 14, that contains no genes or loci known to be involved in the development of any type of cardiomyopathy. This discovery of a DCM locus with a previously unknown etiology will provide a new gene to examine in human DCM patients and a model for testing therapeutic approaches for heart failure.

  19. Knock-in of Enhanced Green Fluorescent Protein or/and Human Fibroblast Growth Factor 2 Gene into β-Casein Gene Locus in the Porcine Fibroblasts to Produce Therapeutic Protein.

    Science.gov (United States)

    Lee, Sang Mi; Kim, Ji Woo; Jeong, Young-Hee; Kim, Se Eun; Kim, Yeong Ji; Moon, Seung Ju; Lee, Ji-Hye; Kim, Keun-Jung; Kim, Min-Kyu; Kang, Man-Jong

    2014-11-01

    Transgenic animals have become important tools for the production of therapeutic proteins in the domestic animal. Production efficiencies of transgenic animals by conventional methods as microinjection and retrovirus vector methods are low, and the foreign gene expression levels are also low because of their random integration in the host genome. In this study, we investigated the homologous recombination on the porcine β-casein gene locus using a knock-in vector for the β-casein gene locus. We developed the knock-in vector on the porcine β-casein gene locus and isolated knock-in fibroblast for nuclear transfer. The knock-in vector consisted of the neomycin resistance gene (neo) as a positive selectable marker gene, diphtheria toxin-A gene as negative selection marker, and 5' arm and 3' arm from the porcine β-casein gene. The secretion of enhanced green fluorescent protein (EGFP) was more easily detected in the cell culture media than it was by western blot analysis of cell extract of the HC11 mouse mammary epithelial cells transfected with EGFP knock-in vector. These results indicated that a knock-in system using β-casein gene induced high expression of transgene by the gene regulatory sequence of endogenous β-casein gene. These fibroblasts may be used to produce transgenic pigs for the production of therapeutic proteins via the mammary glands.

  20. Locus: mede-ontwikkelaar van inclusieve arbeidsorganisaties

    NARCIS (Netherlands)

    Beukema, Leni; de Lange, Annet; Wielenga-Meijer, Etty; Duijker, Theo; Hanstede, Bram

    2018-01-01

    in deze bijdrage wordt Locus beschreven, een netwerk waarin publieke partijen en grote, landelijk opererende bedrijven samenwerken om mensen met een afstand tot de arbeidsmarkt duurzaam aan het werk te helpen. Het hoofdstuk start met de ontstaansgeschiedenis en benadering van Locus. Vervolgens wordt

  1. EL LOCUS DE DISTRIBUCION COMO COROLARIO DEL LOCUS DE CONTROL

    Directory of Open Access Journals (Sweden)

    Luisa Mayoral

    2009-01-01

    Full Text Available Este es un artículo científico acerca del Locus de Distribución, surgido de un estudio realizado con una población de docentes y alumnos universitarios. Respecto de los primeros, se ha indagado acerca de las atribuciones que se realizaban en torno a las recompensas y sanciones, que ellos distribuían a sus alumnos. Respecto de los segundos, se ha buscado determinar la valoración que estos realizaban de sus profesores, en términos de aquellas atribuciones. Para ello, se utilizaron dos paradigmas clásicamente empleados para verificar la existencia de una norma: el paradigma de la autopresentación (docentes, y el paradigma de los juicios (alumnos. La cuestión planteada fue determinar si en el caso de los comportamientos distributivos de refuerzos, las causas se atribuían a variables externas -en particular a los receptores de esos refuerzos- y si esas formas de atribución eran conocidas y valoradas o no, por los alumnos. De los resultados, surgió la confirmación de nuestra hipótesis de explicaciones externas en materia de comportamientos distributivos de sanciones en el ámbito de la docencia y la valoración positiva de estas atribuciones por los alumnos.

  2. Culture, gender and locus of control

    DEFF Research Database (Denmark)

    Ottsen, Christina Lundsgaard; Johannessen, Kim Berg; Berntsen, Dorthe

    The current study is a cross-cultural comparison between the Middle East and Scandinavia. Two societies that offer a unique opportunity to examine gender differences in personal goals and how goals are affected by locus of control.......The current study is a cross-cultural comparison between the Middle East and Scandinavia. Two societies that offer a unique opportunity to examine gender differences in personal goals and how goals are affected by locus of control....

  3. A large duplication involving the IHH locus mimics acrocallosal syndrome.

    Science.gov (United States)

    Yuksel-Apak, Memnune; Bögershausen, Nina; Pawlik, Barbara; Li, Yun; Apak, Selcuk; Uyguner, Oya; Milz, Esther; Nürnberg, Gudrun; Karaman, Birsen; Gülgören, Ayan; Grzeschik, Karl-Heinz; Nürnberg, Peter; Kayserili, Hülya; Wollnik, Bernd

    2012-06-01

    Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a ∼600-kb deletion 5' of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a ∼900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35.

  4. Ancient roots for polymorphism at the HLA-DQ. alpha. locus in primates

    Energy Technology Data Exchange (ETDEWEB)

    Gyllensten, U.B.; Erlich, H.A. (Cetus Corp., Emeryville, CA (USA))

    1989-12-01

    The genes encoding the human histocompatibility antigens (HLA) exhibit a remarkable degree of polymorphism as revealed by immunologic and molecular analyses. This extensive sequence polymorphism either may have been generated during the lifetime of the human species or could have arisen before speciation and been maintained in the contemporary human population by selection or, possibly, by genetic drift. These two hypotheses were examined using the polymerase chain reaction method to amplify polymorphic sequences from the DQ{alpha} locus, as well as the DX{alpha} locus, an homologous but nonexpressed locus, in a series of primates that diverged at known times. In general, the amino acid sequence of a specific human DQ{alpha} allelic type is more closely related to its chimpanzee or gorilla counterpart than to other human DQ{alpha} alleles. Phylogenetic analysis of the silent nucleotide position changes shows that the similarity of allelic types between species is due to common ancestry rather than convergent evolution. Thus, most of the polymorphism at the DQ{alpha} locus in the human species was already present at least 5 million years ago in the ancestral species that gave rise to the chimpanzee, gorilla, and human lineages. However, one of the DQ{alpha} alleles may have arisen after speciation by recombination between two ancestral alleles.

  5. Genetic association of multiple sclerosis with the marker rs391745 near the endogenous retroviral locus HERV-Fc1: analysis of disease subtypes

    DEFF Research Database (Denmark)

    Hansen, Bettina; Oturai, Annette Bang; Harbo, Hanne F

    2011-01-01

    We have previously described the occurrence of multiple sclerosis (MS) to be associated with human endogenous retroviruses, specifically the X-linked viral locus HERV-Fc1. The aim of this study was to investigate a possible association of the HERV-Fc1 locus with subtypes of MS. MS patients......-Fc1 locus (p = 0.003), while primary progressive disease was not. The ability to see genetic differences between subtypes of MS near this gene speaks for the involvement of the virus HERV-Fc1 locus in modifying the disease course of MS....

  6. Oscillating Evolution of a Mammalian Locus with Overlapping Reading Frames: An XLalphas/ALEX Relay.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available XLalphas and ALEX are structurally unrelated mammalian proteins translated from alternative overlapping reading frames of a single transcript. Not only are they encoded by the same locus, but a specific XLalphas/ALEX interaction is essential for G-protein signaling in neuroendocrine cells. A disruption of this interaction leads to abnormal human phenotypes, including mental retardation and growth deficiency. The region of overlap between the two reading frames evolves at a remarkable speed: the divergence between human and mouse ALEX polypeptides makes them virtually unalignable. To trace the evolution of this puzzling locus, we sequenced it in apes, Old World monkeys, and a New World monkey. We show that the overlap between the two reading frames and the physical interaction between the two proteins force the locus to evolve in an unprecedented way. Namely, to maintain two overlapping protein-coding regions the locus is forced to have high GC content, which significantly elevates its intrinsic evolutionary rate. However, the two encoded proteins cannot afford to change too quickly relative to each other as this may impair their interaction and lead to severe physiological consequences. As a result XLalphas and ALEX evolve in an oscillating fashion constantly balancing the rates of amino acid replacements. This is the first example of a rapidly evolving locus encoding interacting proteins via overlapping reading frames, with a possible link to the origin of species-specific neurological differences.

  7. The LOCUS interface to the MFE database

    International Nuclear Information System (INIS)

    Miner, W.H. Jr.

    1991-01-01

    The MFE database now consists of over 900 shots from TFTR, PDX, PLT, T-10, JT-60, TEXT, JET and ASDEX. A variety of discharge conditions is represented, ranging from single time slice Ohmic discharges to multiple time-slice auxiliary heated discharges. Included with most datasets is a reference that describes the experiment being performed when the data was taken. The MFE database is currently implemented under INGRES on a VAX that is on Internet. LOCUS, a database utility, developed at the Princeton Plasma Physics Laboratory is now available as an interface to the database. The LOCUS front end provides a graphic interface to the database from any generic graphics terminal that supports Tektronix 4010 emulation. It provides a variety of procedures for extracting, manipulating and graphing data from the MFE database. In order to demonstrate the capabilities of the LOCUS interface, the authors examine, in detail, one of the recently added JET, H-mode discharges. In this example, they address some new concepts such as monitor functions, which have been introduced in order to help users more fully understand the multiple time-slice datasets. They also describe some of the more advanced techniques available in LOCUS for data access and manipulation. Specific areas of interest that are discussed are searching for and retrieving datasets, graphics, data fitting, and linear regression analysis

  8. The MHC locus and genetic susceptibility to autoimmune and infectious diseases

    NARCIS (Netherlands)

    Matzaraki, Vasiliki; Kumar, Vinod; Wijmenga, Cisca; Zhernakova, Alexandra

    2017-01-01

    In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic

  9. The Impact of Locus of Control on Language Achievement

    Science.gov (United States)

    Nodoushan, Mohammad Ali Salmani

    2012-01-01

    This study hypothesized that students' loci of control affected their language achievement. 198 (N = 198) EFL students took the Rotter's (1966) locus of control test and were classified as locus-internal (ni = 78), and locus-external (ne = 120). They then took their ordinary courses and at the end of the semester, they were given their exams.…

  10. Self-Esteem, Locus of Control, and Student Achievement.

    Science.gov (United States)

    Sterbin, Allan; Rakow, Ernest

    The direct effects of locus of control and self-esteem on standardized test scores were studied. The relationships among the standardized test scores and measures of locus of control and self-esteem for 12,260 students from the National Education Longitudinal Study 1994 database were examined, using the same definition of locus of control and…

  11. Locus of Control and Career Interest of Sophomore Accountancy Students: Basis for Employment Path

    Directory of Open Access Journals (Sweden)

    Jovielyn Mañibo

    2014-02-01

    Full Text Available This academic undertaking sought to determine the relationship between the locus of control and career interest of the respondents towards their future employment. The objectives of the study were to determine the respondents’ locus of control and career interest; to find if there is a significant relationship between the respondents’ locus of control and career interest and to develop an action plan that will gauge the students’ employment success as to their chosen field. In measuring and finding the relationship between the variables of the study, the researchers employed the quantitative method in the analysis of data using the questionnaires for locus of control (LOC and Career Cluster Interest Survey (CCIS as dominant tools. The participants chosen from this study were 74sophomore Accountancy students for Second Semester, School Year 2012 – 2013. Based from the results, most of the respondents (74 sophomore accountancy students have an external locus of control with career interest on education and training, human services, and finance. The computed rvalues indicates slight positive correlation, however, careers on government services, manufacturing , public administration, health science, human services showed significant correlation to internal (positive and external (negative locus of control. .Likewise, the Counseling and Testing Center of the university should conduct cognitive training targeting reasoning and speed of processing that can improve sense of personal control over one’s life and facilitate career orientation during the student- applicants’ admission as regards to their National Career Assessment Examination (NCAE results. With the findings of the study, a program design was created to gauge students employment path.

  12. Characterization of histone H3K27 modifications in the β-globin locus

    International Nuclear Information System (INIS)

    Kim, Yea Woon; Kim, AeRi

    2011-01-01

    Research highlights: → The β-globin locus control region is hyperacetylated and monomethylated at histone H3K27. → Highly transcribed globin genes are marked by H3K27ac, but H3K27me2 is remarkable at silent globin genes in erythroid K562 cells. → Association of PRC2 subunits is comparable with H3K27me3 pattern. → Modifications of histone H3K27 are established in an enhancer-dependent manner. -- Abstract: Histone H3K27 is acetylated or methylated in the environment of nuclear chromatin. Here, to characterize the modification pattern of H3K27 in locus control region (LCR) and to understand the correlation of various H3K27 modifications with transcriptional activity of genes, we analyzed the human β-globin locus using the ChIP assay. The LCR of the human β-globin locus was enriched by H3K27ac and H3K27me1 in erythroid K562 cells. The highly transcribed globin genes were hyperacetylated at H3K27, but the repressed globin genes were highly dimethylated at this lysine in these cells. However, in non-erythroid 293FT cells, the β-globin locus was marked by a high level of H3K27me3. EZH2 and SUZ12, subunits of polycomb repressive complex 2, were comparably detected with the H3K27me3 pattern in K562 and 293FT cells. In addition, H3K27ac, H3K27me1 and H3K27me3 were established in an enhancer-dependent manner in a model minichromosomal locus containing an enhancer and its target gene. Taken together, these results show that H3K27 modifications have distinctive correlations with the chromatin state or transcription level of genes and are influenced by an enhancer.

  13. Role of Oculoproprioception in Coding the Locus of Attention.

    Science.gov (United States)

    Odoj, Bartholomaeus; Balslev, Daniela

    2016-03-01

    The most common neural representations for spatial attention encode locations retinotopically, relative to center of gaze. To keep track of visual objects across saccades or to orient toward sounds, retinotopic representations must be combined with information about the rotation of one's own eyes in the orbits. Although gaze input is critical for a correct allocation of attention, the source of this input has so far remained unidentified. Two main signals are available: corollary discharge (copy of oculomotor command) and oculoproprioception (feedback from extraocular muscles). Here we asked whether the oculoproprioceptive signal relayed from the somatosensory cortex contributes to coding the locus of attention. We used continuous theta burst stimulation (cTBS) over a human oculoproprioceptive area in the postcentral gyrus (S1EYE). S1EYE-cTBS reduces proprioceptive processing, causing ∼1° underestimation of gaze angle. Participants discriminated visual targets whose location was cued in a nonvisual modality. Throughout the visual space, S1EYE-cTBS shifted the locus of attention away from the cue by ∼1°, in the same direction and by the same magnitude as the oculoproprioceptive bias. This systematic shift cannot be attributed to visual mislocalization. Accuracy of open-loop pointing to the same visual targets, a function thought to rely mainly on the corollary discharge, was unchanged. We argue that oculoproprioception is selective for attention maps. By identifying a potential substrate for the coupling between eye and attention, this study contributes to the theoretical models for spatial attention.

  14. Characterization of mutations at the mouse phenylalanine hydroxylase locus

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, J.D.; Charlton, C.K. [Wichita State Univ., KS (United States)

    1997-02-01

    Two genetic mouse models for human phenylketonuria have been characterized by DNA sequence analysis. For each, a distinct mutation was identified within the protein coding sequence of the phenylalanine hydroxylase gene. This establishes that the mutated locus is the same as that causing human phenylketonuria and allows a comparison between these mouse phenylketonuria models and the human disease. A genotype/phenotype relationship that is strikingly similar to the human disease emerges, underscoring the similarity of phenylketonuria in mouse and man. In PAH{sup ENU1}, the phenotype is mild. The Pah{sup enu1} mutation predicts a conservative valine to alanine amino acid substitution and is located in exon 3, a gene region where serious mutations are rare in humans. In PAH{sup ENU2} the phenotype is severe. The Pah{sup enu2} mutation predicts a radical phenylalanine to serine substitution and is located in exon 7, a gene region where serious mutations are common in humans. In PAH{sup ENU2}, the sequence information was used to devise a direct genotyping system based on the creation of a new Alw26I restriction endonuclease site. 26 refs., 2 figs., 1 tab.

  15. Pleiotropic roles of Clostridium difficile sin locus

    Science.gov (United States)

    Ou, Junjun; Dupuy, Bruno

    2018-01-01

    Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR’, coding for SinR (112 aa) and SinR’ (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus’s role in C. difficile physiology. Transcriptome analysis of the sinRR’ mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR’ acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis. PMID:29529083

  16. The algebraic locus of Feynman integrals

    OpenAIRE

    Kol, Barak

    2016-01-01

    In the Symmetries of Feynman Integrals (SFI) approach, a diagram's parameter space is foliated by orbits of a Lie group associated with the diagram. SFI is related to the important methods of Integrations By Parts and of Differential Equations. It is shown that sometimes there exist a locus in parameter space where the set of SFI differential equations degenerates into an algebraic equation, thereby enabling a solution in terms of integrals associated with degenerations of the diagram. This i...

  17. Bipolar disorder: Evidence for a major locus

    Energy Technology Data Exchange (ETDEWEB)

    Spence, M.A.; Flodman, P.L. [Univ. of California, Irvine, CA (United States); Sadovnick, A.D.; Ameli, H. [Univ. of British Columbia, Vancouver (Canada)] [and others

    1995-10-09

    Complex segregation analyses were conducted on families of bipolar I and bipolar II probands to delineate the mode of inheritance. The probands were ascertained from consecutive referrals to the Mood Disorder Service, University Hospital, University of British Columbia and diagnosed by DSM-III-R and Research Diagnostic Criteria. Data were available on over 1,500 first-degree relatives of the 186 Caucasian probands. The purpose of the analyses was to determine if, after correcting for age and birth cohort, there was evidence for a single major locus. Five models were fit to the data using the statistical package SAGE: (1) dominant, (2) recessive, (3) arbitrary mendelian inheritance, (4) environmental, and (5) no major effects. A single dominant, mendelian major locus was the best fitting of these models for the sample of bipolar I and II probands when only bipolar relatives were defined as affected (polygenic inheritance could not be tested). Adding recurrent major depression to the diagnosis {open_quotes}affected{close_quotes} for relatives reduced the evidence for a major locus effect. Our findings support the undertaking of linkage studies and are consistent with the analyses of the National Institutes of Mental Health (NIMH) Collaborative Study data by Rice et al. and Blangero and Elston. 39 refs., 4 tabs.

  18. Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Availability in the Locus Coeruleus

    Science.gov (United States)

    Pietrzak, Robert H.; Gallezot, Jean-Dominique; Ding, Yu-Shin; Henry, Shannan; Potenza, Marc N.; Southwick, Steven M.; Krystal, John H.; Carson, Richard E.; Neumeister, Alexander

    2014-01-01

    IMPORTANCE Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. OBJECTIVES To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). MAIN OUTCOMES AND MEASURES The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale. RESULTS The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. CONCLUSIONS AND RELEVANCE These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity

  19. Measurement of locus copy number by hybridisation with amplifiable probes

    Science.gov (United States)

    Armour, John A. L.; Sismani, Carolina; Patsalis, Philippos C.; Cross, Gareth

    2000-01-01

    Despite its fundamental importance in genome analysis, it is only recently that systematic approaches have been developed to assess copy number at specific genetic loci, or to examine genomic DNA for submicroscopic deletions of unknown location. In this report we show that short probes can be recovered and amplified quantitatively following hybridisation to genomic DNA. This simple observation forms the basis of a new approach to determining locus copy number in complex genomes. The power and specificity of multiplex amplifiable probe hybridisation is demonstrated by the simultaneous assessment of copy number at a set of 40 human loci, including detection of deletions causing Duchenne muscular dystrophy and Prader–Willi/Angelman syndromes. Assembly of other probe sets will allow novel, technically simple approaches to a wide variety of genetic analyses, including the potential for extension to high resolution genome-wide screens for deletions and amplifications. PMID:10606661

  20. Measurement of locus copy number by hybridisation with amplifiable probes.

    Science.gov (United States)

    Armour, J A; Sismani, C; Patsalis, P C; Cross, G

    2000-01-15

    Despite its fundamental importance in genome analysis, it is only recently that systematic approaches have been developed to assess copy number at specific genetic loci, or to examine genomic DNA for submicro-scopic deletions of unknown location. In this report we show that short probes can be recovered and amplified quantitatively following hybridisation to genomic DNA. This simple observation forms the basis of a new approach to determining locus copy number in complex genomes. The power and specificity of multiplex amplifiable probe hybridisation is demonstrated by the simultaneous assessment of copy number at a set of 40 human loci, including detection of deletions causing Duchenne muscular dystrophy and Prader-Willi/Angelman syndromes. Assembly of other probe sets will allow novel, technically simple approaches to a wide variety of genetic analyses, including the potential for extension to high resolution genome-wide screens for deletions and amplifications.

  1. Effect of Estrogen on Mutagenesis in Human Mammary Epithelial Cells

    Science.gov (United States)

    2005-06-01

    of hMSH3 and PCNA. " PMS2 Since overexpression of hMSH3 MSH2 was shown to reduce single-base MMR activity (11, 12), we originally -=GAPDH hypothesized...shown in Fig. days. The cells were harvested and extracted for Western blotting. Anti- MLH 1, PMS2 and MSH2 antibodies were purchased from Oncogene.10

  2. Locus of control and online learning

    Directory of Open Access Journals (Sweden)

    Suretha Esterhuysen

    2004-10-01

    Full Text Available The integration of online learning in university courses is considered to be both inevitable and necessary. Thus there is an increasing need to raise awareness among educators and course designers about the critical issues impacting on online learning. The aim of this study, therefore, was to assess the differences between two groups of first-year Business Sciences learners (online and conventional learners in terms of biographic and demographic characteristics and locus of control. The study population consisted of 586 first-year learners of whom 185 completed the Locus of Control Inventory (LCI. The results show that the two groups of learners do not differ statistically significantly from each other with respect to locus of control. The findings and their implications are also discussed. Opsomming Die integrasie van aanlyn-leer in universiteitskursusse word beskou as sowel onafwendbaar as noodsaaklik. Daar is dus ’n toenemende behoefte om bewustheid onder opvoedkundiges en kursusontwerpers te kweek oor die kritiese aspekte wat ’n impak op aanlyn-leer het (Morgan, 1996. Daarom was die doel van hierdie ondersoek om die verskille tussen twee groepe eerstejaarleerders in Bestuurs- en Ekonomiese Wetenskap (aanlyn en konvensionele leerders te bepaal ten opsigte van biografiese en demografiese eienskappe en lokus van beheer. Die populasie het bestaan uit 586 eerstejaarleerders waarvan 185 die Lokus van Beheer Vraelys voltooi het. Die resultate toon dat die twee groepe leerders nie statisties beduidend van mekaar verskil het met betrekking tot lokus van beheer nie. Die bevindinge en implikasies word ook bespreek.

  3. Designing Epigenome Editors: Considerations of Biochemical and Locus Specificities.

    Science.gov (United States)

    Sen, Dilara; Keung, Albert J

    2018-01-01

    The advent of locus-specific protein recruitment technologies has enabled a new class of studies in chromatin biology. Epigenome editors enable biochemical modifications of chromatin at almost any specific endogenous locus. Their locus specificity unlocks unique information including the functional roles of distinct modifications at specific genomic loci. Given the growing interest in using these tools for biological and translational studies, there are many specific design considerations depending on the scientific question or clinical need. Here we present and discuss important design considerations and challenges regarding the biochemical and locus specificities of epigenome editors. These include how to account for the complex biochemical diversity of chromatin; control for potential interdependency of epigenome editors and their resultant modifications; avoid sequestration effects; quantify the locus specificity of epigenome editors; and improve locus specificity by considering concentration, affinity, avidity, and sequestration effects.

  4. Cut Locus Construction using Deformable Simplicial Complexes

    DEFF Research Database (Denmark)

    Misztal, Marek Krzysztof; Bærentzen, Jakob Andreas; Anton, François

    2011-01-01

    In this paper we present a method for appproximating cut loci for a given point p on Riemannian 2D manifolds, closely related to the notion of Voronoi diagrams. Our method finds the cut locus by advecting a front of points equally distant from p along the geodesics originating at p and finding...... the domain to have disk topology. We test our method for tori of revolution and compare our results to the benchmark ones from [2]. The method, however, is generic and can be easily adapted to construct cut loci for other manifolds of genera other than 1....

  5. Characterization of the bovine type I IFN locus: rearrangements, expansions, and novel subfamilies

    Directory of Open Access Journals (Sweden)

    Walker Angela M

    2009-04-01

    Full Text Available Abstract Background The Type I interferons (IFN have major roles in the innate immune response to viruses, a function that is believed to have led to expansion in the number and complexity of their genes, although these genes have remained confined to single chromosomal region in all mammals so far examined. IFNB and IFNE define the limits of the locus, with all other Type I IFN genes except IFNK distributed between these boundaries, strongly suggesting that the locus has broadened as IFN genes duplicated and then evolved into a series of distinct families. Results The Type I IFN locus in Bos taurus has undergone significant rearrangement and expansion compared to mouse and human, however, with the constituent genes separated into two sub-loci separated by >700 kb. The IFNW family is greatly expanded, comprising 24 potentially functional genes and at least 8 pseudogenes. The IFNB (n = 6, represented in human and mouse by one copy, are also present as multiple copies in Bos taurus. The IFNT, which encode a non-virally inducible, ruminant-specific IFN secreted by the pre-implantation conceptus, are represented by three genes and two pseudogenes. The latter have sequences intermediate between IFNT and IFNW. A new Type I IFN family (IFNX of four members, one of which is a pseudogene, appears to have diverged from the IFNA lineage at least 83 million years ago, but is absent in all other sequenced genomes with the possible exception of the horse, a non-ruminant herbivore. Conclusion In summary, we have provided the first comprehensive annotation of the Type I IFN locus in Bos taurus, thereby providing an insight into the functional evolution of the Type I IFN in ruminants. The diversity and global spread of the ruminant species may have required an expansion of the Type I IFN locus and its constituent genes to provide broad anti-viral protection required for foraging and foregut fermentation.

  6. Relationships between locus of control and paranormal beliefs.

    Science.gov (United States)

    Newby, Robert W; Davis, Jessica Boyette

    2004-06-01

    The present study investigated the associations between scores on paranormal beliefs, locus of control, and certain psychological processes such as affect and cognitions as measured by the Linguistic Inquiry and Word Count. Analysis yielded significant correlations between scores on Locus of Control and two subscales of Tobacyk's (1988) Revised Paranormal Beliefs Scale, New Age Philosophy and Traditional Paranormal Beliefs. A step-wise multiple regression analysis indicated that Locus of Control was significantly related to New Age Philosophy. Other correlations were found between Tobacyk's subscales, Locus of Control, and three processes measured by the Linguistic Inquiry and Word Count.

  7. Impact of locus of control on health message effectiveness.

    Science.gov (United States)

    Kong, Ying; Shen, Fuyuan

    2011-10-01

    This article examined how individuals' locus of control might moderate the effect of health message frames. An experiment was conducted whereby participants read either individual- or social-responsibility message frames after their locus of control was primed. Results indicated that messages presented in individual-responsibility frames were more persuasive when people were primed with internal locus of control, whereas social-responsibility framed appeals were more persuasive when people were primed with external locus of control. These results were found for individuals in both high and low cognitive load conditions. Theoretical and practical implications of the findings are discussed.

  8. A genetic map of mouse chromosome 1 near the Lsh-Ity-Bcg disease resistance locus.

    Science.gov (United States)

    Mock, B; Krall, M; Blackwell, J; O'Brien, A; Schurr, E; Gros, P; Skamene, E; Potter, M

    1990-05-01

    Isozyme and restriction fragment length polymorphism (RFLP) analyses of backcross progeny, recombinant inbred strains, and congenic strains of mice positioned eight genetic markers with respect to the Lsh-Ity-Bcg disease resistance locus. Allelic isoforms of Idh-1 and Pep-3 and RFLPs detected by Southern hybridization for Myl-1, Cryg, Vil, Achrg, bcl-2, and Ren-1,2, between BALB/cAnPt and DBA/2NPt mice, were utilized to examine the cosegregation of these markers with the Lsh-Ity-Bcg resistance phenotype in 103 backcross progeny. An additional 47 backcross progeny from a cross between C57BL/10ScSn and B10.L-Lshr/s mice were examined for the cosegregation of Myl-1 and Vil RFLPs with Lsh phenotypic differences. Similarly, BXD recombinant inbred strains were typed for RFLPs upon hybridization with Vil and Achrg. Recombination frequencies generated in the different test systems were statistically similar, and villin (Vil) was identified as the molecular marker closest (1.7 +/- 0.8 cM) to the Lsh-Ity-Bcg locus. Two other DNA sequences, nebulin (Neb) and an anonymous DNA fragment (D2S3), which map to a region of human chromosome 2q that is homologous to proximal mouse chromosome 1, were not closely linked to the Lsh-Ity-Bcg locus. This multipoint linkage analysis of chromosome 1 surrounding the Lsh-Ity-Bcg locus provides a basis for the eventual isolation of the disease gene.

  9. The protective influence of the locus ceruleus on the blood-brain barrier

    International Nuclear Information System (INIS)

    Harik, S.I.; McGunigal, T. Jr.

    1984-01-01

    The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines

  10. TALEN/CRISPR-mediated eGFP knock-in add-on at the OCT4 locus does not impact differentiation of human embryonic stem cells towards endoderm.

    Directory of Open Access Journals (Sweden)

    Nicole A J Krentz

    Full Text Available Human embryonic stem cells (hESCs have great promise as a source of unlimited transplantable cells for regenerative medicine. However, current progress on producing the desired cell type for disease treatment has been limited due to an insufficient understanding of the developmental processes that govern their differentiation, as well as a paucity of tools to systematically study differentiation in the lab. In order to overcome these limitations, cell-type reporter hESC lines will be required. Here we outline two strategies using Transcription Activator Like Effector Nucleases (TALENs and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR-CRISPR-Associated protein (Cas to create OCT4-eGFP knock-in add-on hESC lines. Thirty-one and forty-seven percent of clones were correctly modified using the TALEN and CRISPR-Cas9 systems, respectively. Further analysis of three correctly targeted clones demonstrated that the insertion of eGFP in-frame with OCT4 neither significantly impacted expression from the wild type allele nor did the fusion protein have a dramatically different biological stability. Importantly, the OCT4-eGFP fusion was easily detected using microscopy, flow cytometry and western blotting. The OCT4 reporter lines remained equally competent at producing CXCR4+ definitive endoderm that expressed a panel of endodermal genes. Moreover, the genomic modification did not impact the formation of NKX6.1+/SOX9+ pancreatic progenitor cells following directed differentiation. In conclusion, these findings demonstrate for the first time that CRISPR-Cas9 can be used to modify OCT4 and highlight the feasibility of creating cell-type specific reporter hESC lines utilizing genome-editing tools that facilitate homologous recombination.

  11. Evolution of the sex-related locus and genomic features shared in microsporidia and fungi.

    Directory of Open Access Journals (Sweden)

    Soo Chan Lee

    2010-05-01

    Full Text Available Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes.Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21 present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30 that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates and E. hellem (1 isolate. There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians.The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex

  12. Locus - ASTRA | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data ...URL: ftp://ftp.biosciencedbc.jp/archive/astra/LATEST/astra_locus.zip File size: 887 KB Simple search URL htt...icing type (ex. cassette) About This Database Database Description Download License Update History of This Database Site Policy | Contact Us Locus - ASTRA | LSDB Archive ...

  13. Is this Red Spot the Blue Spot (locus ceruleum)?

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Won Sick; Lee, Yu Kyung; Lee, Min Kyung; Hwang, Kyung Hoon [Gachon University Gil Hospital, Incheon (Korea, Republic of)

    2010-06-15

    The authors report brain images of 18F-FDG-PET in a case of schizophrenia. The images showed strikingly increased bilateral uptake in the locus ceruleum. The locus ceruleum is called the blue spot and known to be a center of the norepinephrinergic system.

  14. Metacognition: As a Predictor of One's Academic Locus of Control

    Science.gov (United States)

    Arslan, Serhat; Akin, Ahmet

    2014-01-01

    The purpose of this study is to examine the effect of metacognition on one's academic locus of control. The study's sample group consists of 451 university students enrolled in various programs at Sakarya University, Turkey. In this study, the Metacognitive Awareness Inventory and the Academic Locus of Control Scale were used. The correlations and…

  15. Personality and Locus of Control among School Children

    Science.gov (United States)

    Pandya, Archana A.; Jogsan, Yogesh A.

    2013-01-01

    The main purpose of this investigation is to find out the sex differences in personality traits and locus of control among school children. A total 60 children (30 boys and 30 girls) were taken as a sample. The research tool for personality, children personality questionnaire was used, which was made by Cattell and Porter. Locus of control was…

  16. Physical Attractiveness, Locus of Control, Sex Role, and Conversational Assertiveness.

    Science.gov (United States)

    Campbell, Keith F.; And Others

    1990-01-01

    Analyzes the relationship among physical attractiveness, locus of control, sex role orientation, and assertiveness in undergraduate students. Reviews videotapes of mixed-sex student groups engaged in discussion. Finds an internal locus of control positively correlated with assertiveness. Uses a behavioral measure of assertiveness rather than…

  17. Locus of control and investment in risky assets

    NARCIS (Netherlands)

    Salamanca Acosta, N.; de Grip, A.; Fouarge, D.; Montizaan, R.M.

    2013-01-01

    Using representative household panel data, we show that the investment behavior of households is related to the economic locus of control of household heads. A household’s internal locus of control in economic issues is positively related to its decision to hold risky assets as well as its share of

  18. Locus of control and investment in risky assets

    NARCIS (Netherlands)

    Salamanca, N.; de Grip, A.; Fouarge, D.; Montizaan, R.M.

    2013-01-01

    Using representative household panel data, we show that the investment behavior of households is related to the economic locus of control of household heads. A household's internal locus of control in economic issues is positively related to its decision to hold risky assets as well as its share of

  19. Is this Red Spot the Blue Spot (locus ceruleum)?

    International Nuclear Information System (INIS)

    Choe, Won Sick; Lee, Yu Kyung; Lee, Min Kyung; Hwang, Kyung Hoon

    2010-01-01

    The authors report brain images of 18F-FDG-PET in a case of schizophrenia. The images showed strikingly increased bilateral uptake in the locus ceruleum. The locus ceruleum is called the blue spot and known to be a center of the norepinephrinergic system.

  20. Escala de Locus de controle ELCO/TELEBRÁS Scale of Locus of control - ELCO

    Directory of Open Access Journals (Sweden)

    Luiz Pasquali

    1998-01-01

    Full Text Available Com base na teoria de Rotter e Escala de Levenson foi elaborada uma escala de Locus de Controle Organizacional (ELCO, composta por 28 itens. A escala foi validada com uma amostra de 350 empregados do Sistema Telebrás. Verificou-se a presença dos 2 fatores previstos na teoria, a saber: internalidade e externalidade, aparecendo a escala de externalidade, com 18 itens, bem estruturada (alfa = 0.81 e a de internalidade, com 10 itens, deixando a desejar no que se refere à consistência interna (alfa = 0.66. Com os dados desta pesquisa foi feita também análise do Locus de Controle desses mesmos empregados. A constatação mais saliente foi a de que o nível de internalidade caiu com o aumento do nível escolar e o aumento da experiência profissional desses mesmos empregados. Estes resultados surpreendentes foram interpretados em termos da situação típica da empresa, que está passando por um período de transição, a saber: a passagem da condição de empresa estatal para empresa privada, o que seria motivo da perda de confiança dos empregados na própria competência, particularmente por parte daqueles com maior competência intelectual e maior experiência profissional. Fez-se igualmente reparos na qualidade psicométrica da escala e da própria teoria do Locus de controle, no sentido de que esta precisa ser melhor axiomatizada para possibilitar a elaboração de escalas mais precisas para a medida dos construtos que propõe.A scale with 28 items, the Organizational Locus of Control (ELCO, was built based on Rotter’s theory and Levenson’s scale. ELCO was validated on a sample of 350 employees of Telebrás, a governmental firm in Brazil. As foreseen from the theory, a principal-axis factoring showed the presence of the expected two factors, namely internal and external locus of control. The external locus of control factor, composed of 18 items, showed good internal consistency (alpha =.81 whereas the internal factor, with 10 items

  1. Genome-wide association study identifies a novel canine glaucoma locus.

    Directory of Open Access Journals (Sweden)

    Saija J Ahonen

    Full Text Available Glaucoma is an optic neuropathy and one of the leading causes of blindness. Its hereditary forms are classified into primary closed-angle (PCAG, primary open-angle (POAG and primary congenital glaucoma (PCG. Although many loci have been mapped in human, only a few genes have been identified that are associated with the development of glaucoma and the genetic basis of the disease remains poorly understood. Glaucoma has also been described in many dog breeds, including Dandie Dinmont Terriers (DDT in which it is a late-onset (>7 years disease. We designed clinical and genetic studies to better define the clinical features of glaucoma in the DDT and to identify the genetic cause. Clinical diagnosis was based on ophthalmic examinations of the affected dogs and 18 additionally investigated unaffected DDTs. We collected DNA from over 400 DTTs and a genome wide association study was performed in a cohort of 23 affected and 23 controls, followed by a fine mapping, a replication study and candidate gene sequencing. The clinical study suggested that ocular abnormalities including abnormal iridocorneal angles and pectinate ligament dysplasia are common (50% and 72%, respectively in the breed and the disease resembles human PCAG. The genetic study identified a novel 9.5 Mb locus on canine chromosome 8 including the 1.6 Mb best associated region (p = 1.63 × 10(-10, OR = 32 for homozygosity. Mutation screening in five candidate genes did not reveal any causative variants. This study indicates that although ocular abnormalities are common in DDTs, the genetic risk for glaucoma is conferred by a novel locus on CFA8. The canine locus shares synteny to a region in human chromosome 14q, which harbors several loci associated with POAG and PCG. Our study reveals a new locus for canine glaucoma and ongoing molecular studies will likely help to understand the genetic etiology of the disease.

  2. Characterization of a hypoxia-response element in the Epo locus of the pufferfish, Takifugu rubripes.

    Science.gov (United States)

    Kulkarni, Rashmi P; Tohari, Sumanty; Ho, Adrian; Brenner, Sydney; Venkatesh, Byrappa

    2010-06-01

    Animals respond to hypoxia by increasing synthesis of the glycoprotein hormone erythropoietin (Epo) which in turn stimulates the production of red blood cells. The gene encoding Epo has been recently cloned in teleost fishes such as the pufferfish Takifugu rubripes (fugu) and zebrafish (Danio rerio). It has been shown that the transcription levels of Epo in teleost fishes increase in response to anemia or hypoxia in a manner similar to its human ortholog. However, the cis-regulatory element(s) mediating the hypoxia response of Epo gene in fishes has not been identified. In the present study, using the human hepatoma cell line (Hep3B), we have identified and characterized a hypoxia response element (HRE) in the fugu Epo locus. The sequence of the fugu HRE (ACGTGCTG) is identical to that of the HRE in the human EPO locus. However, unlike the HRE in the mammalian Epo locus, which is located in the 3' region of the gene, the fugu HRE is located in the 5' flanking region and on the opposite strand of DNA. This HRE is conserved in other teleosts such as Tetraodon and zebrafish in a similar location. A 365-bp fragment containing the fugu HRE was able to drive GFP expression in the liver of transgenic zebrafish. However, we could not ascertain if the expression of transgene is induced by hypoxia in vivo due to the low and variable levels of GFP expression in transgenic zebrafish. Our investigations also revealed that the Epo locus has experienced extensive rearrangements during vertebrate evolution. Copyright © 2010 Elsevier B.V. All rights reserved.

  3. Imported brucellosis in Denmark: Molecular identification and multiple-locus variable number tandem repeat analysis (MLVA) genotyping of the bacteria

    DEFF Research Database (Denmark)

    Aftab, H.; Dargis, R.; Christensen, J. J.

    2011-01-01

    A polymerase chain reaction was used to identify Brucella species isolated from humans in Denmark. Consecutive analysis of referred bacteria and re-examination of historical isolates identified all as Brucella melitensis. Multiple-locus variable number tandem repeat analysis (MLVA) placed...... the isolates in the previously defined 'East Mediterranean' B. melitensis group....

  4. Health Locus of Control尺度開発の歴史(社会科学編)

    OpenAIRE

    吉田, 由美; Yumi, YOSHIDA; 千葉県立衛生短期大学(看護学); Chiba College of Health Science

    1994-01-01

    This article describes the origins history of Health Locus of Control scales. First, Rotter's social learing theory, which is the theoretical background of the Health Locus of Control construct, is outlined. The scale and research trends of Locus of Control concept, and those of Health Locus of Control concept which are based on Locus of Control, are then reviewed. Finally, Health Locus of Control is discussed with regard to the implications for health education.

  5. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus

    Science.gov (United States)

    Sears, Robert M.; Fink, Ann E.; Wigestrand, Mattis B.; Farb, Claudia R.; de Lecea, Luis; LeDoux, Joseph E.

    2013-01-01

    Survival in a dangerous environment requires learning about stimuli that predict harm. Although recent work has focused on the amygdala as the locus of aversive memory formation, the hypothalamus has long been implicated in emotional regulation, and the hypothalamic neuropeptide orexin (hypocretin) is involved in anxiety states and arousal. Nevertheless, little is known about the role of orexin in aversive memory formation. Using a combination of behavioral pharmacology, slice physiology, and optogenetic techniques, we show that orexin acts upstream of the amygdala via the noradrenergic locus coeruleus to enable threat (fear) learning, specifically during the aversive event. Our results are consistent with clinical studies linking orexin levels to aversive learning and anxiety in humans and dysregulation of the orexin system may contribute to the etiology of fear and anxiety disorders. PMID:24277819

  6. Impact of variation at the FTO locus on milk fat yield in Holstein dairy cattle.

    Science.gov (United States)

    Zielke, Lea G; Bortfeldt, Ralf H; Reissmann, Monika; Tetens, Jens; Thaller, Georg; Brockmann, Gudrun A

    2013-01-01

    This study explores the biological role of the Fat Mass and Obesity associated (FTO) gene locus on milk composition in German Holstein cattle. Since FTO controls energy homeostasis and expenditure and the FTO locus has repeatedly shown association with obesity in human studies, we tested FTO as a candidate gene in particular for milk fat yield, which represents a high amount of energy secreted during lactation. The study was performed on 2,402 bulls and 860 cows where dense milk composition data were available. Genetic information was taken from a 2 Mb region around FTO. Five SNPs and two haplotype blocks in a 725 kb region covering FTO and the neighboring genes RPGRIP1L, U6ATAC, and 5 S rRNA were associated with milk fat yield and also affected protein yield in the same direction. Interestingly, higher frequency SNP alleles and haplotypes within the FTO gene increased milk fat and protein yields by up to 2.8 and 2.2 kg per lactation, respectively, while the most frequent haplotype in the upstream block covering exon 1 of FTO to exon 15 of RPGRIP1L had opposite effects with lower fat and milk yield. Both haplotype blocks were also significant in cows. The loci accounted for about 1% of the corresponding trait variance in the population. The association signals not only provided evidence for at least two causative mutations in the FTO locus with a functional effect on milk but also milk protein yield. The pleiotropic effects suggest a biological function on the usage of energy resources and the control of energy balance rather than directly affecting fat and protein synthesis. The identified effect of the obesity gene locus on milk energy content suggests an impact on infant nutrition by breast feeding in humans.

  7. Impact of variation at the FTO locus on milk fat yield in Holstein dairy cattle.

    Directory of Open Access Journals (Sweden)

    Lea G Zielke

    Full Text Available This study explores the biological role of the Fat Mass and Obesity associated (FTO gene locus on milk composition in German Holstein cattle. Since FTO controls energy homeostasis and expenditure and the FTO locus has repeatedly shown association with obesity in human studies, we tested FTO as a candidate gene in particular for milk fat yield, which represents a high amount of energy secreted during lactation. The study was performed on 2,402 bulls and 860 cows where dense milk composition data were available. Genetic information was taken from a 2 Mb region around FTO. Five SNPs and two haplotype blocks in a 725 kb region covering FTO and the neighboring genes RPGRIP1L, U6ATAC, and 5 S rRNA were associated with milk fat yield and also affected protein yield in the same direction. Interestingly, higher frequency SNP alleles and haplotypes within the FTO gene increased milk fat and protein yields by up to 2.8 and 2.2 kg per lactation, respectively, while the most frequent haplotype in the upstream block covering exon 1 of FTO to exon 15 of RPGRIP1L had opposite effects with lower fat and milk yield. Both haplotype blocks were also significant in cows. The loci accounted for about 1% of the corresponding trait variance in the population. The association signals not only provided evidence for at least two causative mutations in the FTO locus with a functional effect on milk but also milk protein yield. The pleiotropic effects suggest a biological function on the usage of energy resources and the control of energy balance rather than directly affecting fat and protein synthesis. The identified effect of the obesity gene locus on milk energy content suggests an impact on infant nutrition by breast feeding in humans.

  8. EL LOCUS DE DISTRIBUCION COMO COROLARIO DEL LOCUS DE CONTROL (THE LOCUS OF DISTRIBUTION AS A COROLLARY TO THE LOCUS OF CONTROL

    Directory of Open Access Journals (Sweden)

    Mayoral Luisa

    2009-08-01

    Full Text Available Resumen: Este es un artículo científico acerca del Locus de Distribución, surgido de un estudio realizado con una población de docentes y alumnos universitarios. Respecto de los primeros, se ha indagado acerca de las atribuciones que se realizaban en torno a las recompensas y sanciones, que ellos distribuían a sus alumnos.Respecto de los segundos, se ha buscado determinar la valoración que estos realizaban de sus profesores, en términos de aquellas atribuciones. Para ello, se utilizaron dos paradigmas clásicamente empleados para verificar la existencia de una norma: el paradigma de la autopresentación (docentes, y el paradigma de los j uicios (alumnos. La cuestión planteada fue determinar si en el caso de los comportamientos distributivos de refuerzos, las causas se atribuían a variables externas -en particular a los receptores de esos refuerzos- y si esas formas de atribución eran conocidas y valoradas o no, por los alumnos. De los resultados, surgió la confirmación de nuestra hipótesis de explicaciones externas en materia de comportamientos distributivos de sanciones en el ámbito de la docencia y la valoración positiva de estas atribuciones por los alumnos.Abstract:This one is a scientific article brings over of the Locus of Distribution, arisen from a study realized with a population of teachers and university pupils. Respect of the first ones, it has been investigated brings over of the attributions that were concerning around the reinforcements which they were distributing to pupils. Respect of the second ones, one has sought to determine the valuation that these realized of the teachers, in terms of those attributions. For it, two paradigms were in use classic used to check the existence of a norm: the paradigm of the auto-presentation (teachers, and the paradigm of the judgments (pupils The raised question was to determine if in case of the distributive behaviours of reinforcements, the reasons were assuming to external

  9. Relation of organizational citizenship behavior and locus of control.

    Science.gov (United States)

    Turnipseed, David L; Bacon, Calvin M

    2009-12-01

    The relation of organizational citizenship behavior and locus of control was assessed in a sample of 286 college students (52% men; M age = 24 yr.) who worked an average of 26 hr. per week. Measures were Spector's Work Locus of Control Scale and Podsakoff, et al.'s Organization Citizenship Behavior scale. Hierarchical multiple regressions indicated positive association of scores on work locus of control with scores on each of the four tested dimensions of organizational citizenship, as well as total organizational citizenship behavior.

  10. Autism, fever, epigenetics and the locus coeruleus.

    Science.gov (United States)

    Mehler, Mark F; Purpura, Dominick P

    2009-03-01

    Some children with autism spectrum disorders (ASD) exhibit improved behaviors and enhanced communication during febrile episodes. We hypothesize that febrigenesis and the behavioral-state changes associated with fever in autism depend upon selective normalization of key components of a functionally impaired locus coeruleus-noradrenergic (LC-NA) system. We posit that autistic behaviors result from developmental dysregulation of LC-NA system specification and neural network deployment and modulation linked to the core behavioral features of autism. Fever transiently restores the modulatory functions of the LC-NA system and ameliorates autistic behaviors. Fever-induced reversibility of autism suggests preserved functional integrity of widespread neural networks subserving the LC-NA system and specifically the subsystems involved in mediating the cognitive and behavioral repertoires compromised in ASD. Alterations of complex gene-environmental interactions and associated epigenetic mechanisms during seminal developmental critical periods are viewed as instrumental in LC-NA dysregulation as emphasized by the timing and severity of prenatal maternal stressors on autism prevalence. Our hypothesis has implications for a rational approach to further interrogate the interdisciplinary etiology of ASD and for designing novel biological detection systems and therapeutic agents that target the LC-NA system's diverse network of pre- and postsynaptic receptors, intracellular signaling pathways and dynamic epigenetic remodeling processes involved in their regulation and functional plasticity.

  11. Locus coeruleus and dopaminergic consolidation of everyday memory

    Science.gov (United States)

    Takeuchi, Tomonori; Duszkiewicz, Adrian J.; Sonneborn, Alex; Spooner, Patrick A.; Yamasaki, Miwako; Watanabe, Masahiko; Smith, Caroline C.; Fernández, Guillén; Deisseroth, Karl; Greene, Robert W.; Morris, Richard G. M.

    2016-01-01

    Summary The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine hydroxylase-expressing (TH+) neurons in the ventral tegmental area (VTA). We report that neuronal firing in the locus coeruleus (LC) is especially sensitive to environmental novelty, LC-TH+ neurons project more profusely than VTA-TH+ neurons to the hippocampus, optogenetic activation of LC-TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by VTA inactivation. Surprisingly, two effects of LC-TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptors blockade – memory enhancement and long lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, LC-TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in hippocampus. PMID:27602521

  12. Detection of a molecular deletion at the DXS732 locus in a patient with X-linked hypohidrotic ectodermal dysplasia (EDA), with the identification of a unique junctional fragment

    Energy Technology Data Exchange (ETDEWEB)

    Zonana, J.; Gault, J.; Jones, M.; Browne, D.; Litt, M. (Oregon Health Sciences Univ., Portland (United States)); Davies, K.J.P.; Clarke, A.; Thomas, N.S.T. (Univ. of Wales, Cardiff (United Kingdom)); Brockdorff, N.; Rastan, S. (Medical Research Council Clinical Research Centre, Harrow (United Kingdom))

    1993-01-01

    X-linked hypohidrotic ectodermal dysplasia (EDA) has been localized to the Xq12-q13.1. A panel of genomic DNA samples from 80 unrelated males with EDA has been screened for deletions at seven genetic loci within the Xq12-13 region. A single individual was identified with a deletion at the DXS732 locus by hybridization with the mouse genomic probe pcos169E/4. This highly conserved DNA probe is from locus DXCrc169, which is tightly linked to the Ta locus, the putative mouse homologue of EDA. The proband had the classical phenotype of EDA, with no other phenotypic abnormalities, and a normal cytogenetic analysis. A human genomic DNA clone, homologous to pcos169E/4, was isolated from a human X-chromosome cosmid library. On hybridization with the cosmid, the proband was found to be only partially deleted at the DXS732 locus, with a unique junctional fragment identified in the proband and in three of his maternal relatives. This is the first determination of carrier status for EDA in females, by direct mutation analysis. Failure to detect deletion of the other loci tested in the proband suggests that the DXS732 locus is the closest known locus to the EDA gene. Since the DXS732 locus contains a highly conserved sequence, it must be considered to be a candidate locus for the EDA gene itself. 18 refs., 3 figs., 1 tab.

  13. Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis.

    Science.gov (United States)

    Mocellin, Simone; Verdi, Daunia; Pooley, Karen A; Landi, Maria T; Egan, Kathleen M; Baird, Duncan M; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

    2012-06-06

    rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.

  14. Multidimensional profiles of health locus of control in Hispanic Americans.

    Science.gov (United States)

    Champagne, Brian R; Fox, Rina S; Mills, Sarah D; Sadler, Georgia Robins; Malcarne, Vanessa L

    2016-10-01

    Latent profile analysis identified health locus of control profiles among 436 Hispanic Americans who completed the Multidimensional Health Locus of Control scales. Results revealed four profiles: Internally Oriented-Weak, -Moderate, -Strong, and Externally Oriented. The profile groups were compared on sociocultural and demographic characteristics, health beliefs and behaviors, and physical and mental health outcomes. The Internally Oriented-Strong group had less cancer fatalism, religiosity, and equity health attributions, and more alcohol consumption than the other three groups; the Externally Oriented group had stronger equity health attributions and less alcohol consumption. Deriving multidimensional health locus of control profiles through latent profile analysis allows examination of the relationships of health locus of control subtypes to health variables. © The Author(s) 2015.

  15. 240 INFLUENCES OF PEER RELATIONS AND LOCUS OF ...

    African Journals Online (AJOL)

    Financial recklessness is a behavior that has far reaching negative .... between consumer financial knowledge, income and locus of control on financial ... Their interactions with their peers increased their internal motivations and thus helped.

  16. Emotional intelligence and locus of control of adult patients with ...

    African Journals Online (AJOL)

    2011-03-15

    Mar 15, 2011 ... Keywords: breast cancer, treatment, positive psychology, emotional intelligence, locus of control ... branches are organised in a hierarchy with perception of ..... Asian. Development Bank Knowledge Solutions [serial online].

  17. LOCUS OF CONTROL AND JOB SATISFACTION: PSU EMPLOYEES

    Directory of Open Access Journals (Sweden)

    Lakshman Vijayashree

    2011-11-01

    Full Text Available Previous research studies have demonstrated that internal/external locus of control impacts jobsatisfaction. The present study thus aims to analyze type of locus of control and its relation with jobsatisfaction. The study will be of great help for organization to understand and know what type oflocus of control their employees has and how it has an impact on job satisfaction.The objectives of this study were: 1- To identify the type of Locus of Control (i.e. Internal orExternal present in Public Sector Units (PSU in Bangalore and 2- To analyze the impact of differenttype of Locus of Control on job satisfaction of PSU Employees. Further hypothesis was also set tocheck the relationship between locus of control and job satisfaction. In addition, the relationshipbetween different demographic factors was also examined. The tool used for this study was LocoInventory. The concept of locus of control by Levenson (1972 was used to develop Loco Inventory(Locus of Control in Organization Inventory. The survey used a questionnaire, which had thirty fivestatements which highlights the factors that determine the locus of control and job satisfaction levelof the employees. The Ratio, ANOVA, and Correlation analysis were used as statistical techniquesfor analysis.The results indicate that there is a positive correlation between internal locus of control and jobsatisfaction as well as between External (other locus of control and job satisfaction. And in case ofExternal (Chance locus of control and job satisfaction there exists partial positive correlation. As perthis study Job satisfaction level among the employees is also good as the mean is 17, which is closerto maximum scale value of 25. As per ANOVA table there is a significant variance betweeninternality and age as well as between externality (chance and age. There is no significantrelationship between internality and demographic factors like gender and education. There is nosignificant relationship between

  18. The relationship between locus of control and career advancement

    OpenAIRE

    2014-01-01

    M.Com. (Industrial Psychology) The objective which career of this study advancement is was to investigate the extent to contingent on the personality construct locus of control. In order to achieve this, empirical research was conducted in a South African organisation. A survey questionnaire measuring career advancement and locus of control was completed by 152 subjects. The hypothesis which was formulated was that people with higher rates of career advancement would be more internal and t...

  19. Science Study For A Low Cost Upper Atmosphere Sounder (LOCUS)

    Science.gov (United States)

    Gerber, D.; Swinyard, B. M.; Ellison, B. N.; Siddans, R.; Kerridge, B. J.; Plane, J. M. C.; Feng, W.

    2013-12-01

    We present the findings of an initial science study to define the spectral bands for the proposed Mesosphere / Lower Thermosphere (MLT) sounder LOCUS. The LOCUS mission (Fig 1) uses disruptive technologies to make key MLT species detectable globally by satellite remote sensing for the first time. This presentation summarises the technological and scientific foundation on which the current 4-band Terahertz (THz) and sub- millimetre wave (SMW) instrument configuration was conceived.

  20. Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus. [Mice

    Energy Technology Data Exchange (ETDEWEB)

    Nebert, D.W.; Levitt, R.C.; Jensen, N.M.; Lambert, G.H.; Felton, J.S.

    1977-01-01

    The balance between cytochrome(s) P/sub 1/-450 and other forms of P-450 in the liver, and probably many nonhepatic tissues as well, appears to be important in the toxicity, carcinogenicity, mutagenicity, and teratogenicity of numerous compounds. Thus, allelic differences in a single gene--the Ah locus-- can have profound effects on the susceptibility of mice to drug toxicity and cancer. There is evidence for the Ah lous in the human. Striking increases in the incidence of stillborns, reorptions,and malformations caused by 3-methylcholanthrene or 7,12-dimethylbenz(a)anthracene were observed in the aromatic hydrocarbon responsive C57BL/6N,C3H/HeN, and BALB/cAnN inbred strains, compared with the genetically nonresponsive AKR/N. These data suggest that an association exists between the Ah locus and teratogenesis. Although numerous teratogenic differences among inbred mouse strains have been previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance, on the basis of known differences in polycyclic hydrocarbon metabolism regulated by the Ah locus.

  1. DFNB79: reincarnation of a nonsyndromic deafness locus on chromosome 9q34.3.

    Science.gov (United States)

    Khan, Shahid Yar; Riazuddin, Saima; Shahzad, Mohsin; Ahmed, Nazir; Zafar, Ahmad Usman; Rehman, Atteeq Ur; Morell, Robert J; Griffith, Andrew J; Ahmed, Zubair M; Riazuddin, Sheikh; Friedman, Thomas B

    2010-01-01

    Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at theta=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23-q21.1. The nonsyndromic deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.

  2. Fixation probability in a two-locus intersexual selection model.

    Science.gov (United States)

    Durand, Guillermo; Lessard, Sabin

    2016-06-01

    We study a two-locus model of intersexual selection in a finite haploid population reproducing according to a discrete-time Moran model with a trait locus expressed in males and a preference locus expressed in females. We show that the probability of ultimate fixation of a single mutant allele for a male ornament introduced at random at the trait locus given any initial frequency state at the preference locus is increased by weak intersexual selection and recombination, weak or strong. Moreover, this probability exceeds the initial frequency of the mutant allele even in the case of a costly male ornament if intersexual selection is not too weak. On the other hand, the probability of ultimate fixation of a single mutant allele for a female preference towards a male ornament introduced at random at the preference locus is increased by weak intersexual selection and weak recombination if the female preference is not costly, and is strong enough in the case of a costly male ornament. The analysis relies on an extension of the ancestral recombination-selection graph for samples of haplotypes to take into account events of intersexual selection, while the symbolic calculation of the fixation probabilities is made possible in a reasonable time by an optimizing algorithm. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Two-locus linkage analysis in multiple sclerosis (MS)

    Energy Technology Data Exchange (ETDEWEB)

    Tienari, P.J. (National Public Health Institute, Helsinki (Finland) Univ. of Helsinki (Finland)); Terwilliger, J.D.; Ott, J. (Columbia Univ., New York (United States)); Palo, J. (Univ. of Helsinki (Finland)); Peltonen, L. (National Public Health Institute, Helsinki (Finland))

    1994-01-15

    One of the major challenges in genetic linkage analyses is the study of complex diseases. The authors demonstrate here the use of two-locus linkage analysis in multiple sclerosis (MS), a multifactorial disease with a complex mode of inheritance. In a set of Finnish multiplex families, they have previously found evidence for linkage between MS susceptibility and two independent loci, the myelin basic protein gene (MBP) on chromosome 18 and the HLA complex on chromosome 6. This set of families provides a unique opportunity to perform linkage analysis conditional on two loci contributing to the disease. In the two-trait-locus/two-marker-locus analysis, the presence of another disease locus is parametrized and the analysis more appropriately treats information from the unaffected family member than single-disease-locus analysis. As exemplified here in MS, the two-locus analysis can be a powerful method for investigating susceptibility loci in complex traits, best suited for analysis of specific candidate genes, or for situations in which preliminary evidence for linkage already exists or is suggested. 41 refs., 6 tabs.

  4. [Health locus of control of patients in disease management programmes].

    Science.gov (United States)

    Schnee, M; Grikscheit, F

    2013-06-01

    Health locus of control beliefs plays a major role in improving self-management skills of the chronically ill - a main goal in disease management programmes (DMP). This study aims at characterising participants in disease management regarding their health locus of control. Data are based on 4 cross-sectional postal surveys between spring and autumn of 2006 and 2007 within the Health Care Monitor of the Bertelsmann Foundation. Among the 6 285 respondents, 1 266 are chronically ill and not enrolled in a DMP and 327 are participating in a DMP. A high internal locus of control (HLC) occurs significantly less often in DMP patients than in normal chronically ill patients (and healthy people) controlling for age, gender and social class. With increasing age, a high internal locus of control is also significantly less likely. When comparing healthy people, the chronically ill and the DMP participants a social gradient of a high internal locus of control belief can be observed. The weaker internal and higher doctor-related external locus of control of DMP participants should be carefully observed by the physician when trying to strengthen the patients' self-management skills. Evaluators of DMP should take into account the different baselines of DMP patients and relevant control groups and incorporate these differences into the evaluation. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Neurolinguistic programming training, trait anxiety, and locus of control.

    Science.gov (United States)

    Konefal, J; Duncan, R C; Reese, M A

    1992-06-01

    Training in the neurolinguistic programming techniques of shifting perceptual position, visual-kinesthetic dissociation, timelines, and change-history, all based on experiential cognitive processing of remembered events, leads to an increased awareness of behavioral contingencies and a more sensitive recognition of environmental cues which could serve to lower trait anxiety and increase the sense of internal control. This study reports on within-person and between-group changes in trait anxiety and locus of control as measured on the Spielberger State-Trait Anxiety Inventory and Wallston, Wallston, and DeVallis' Multiple Health Locus of Control immediately following a 21-day residential training in neurolinguistic programming. Significant with-in-person decreases in trait-anxiety scores and increases in internal locus of control scores were observed as predicted. Chance and powerful other locus of control scores were unchanged. Significant differences were noted on trait anxiety and locus of control scores between European and U.S. participants, although change scores were similar for the two groups. These findings are consistent with the hypothesis that this training may lower trait-anxiety scores and increase internal locus of control scores. A matched control group was not available, and follow-up was unfortunately not possible.

  6. Identification of rat Rosa26 locus enables generation of knock-in rat lines ubiquitously expressing tdTomato.

    Science.gov (United States)

    Kobayashi, Toshihiro; Kato-Itoh, Megumi; Yamaguchi, Tomoyuki; Tamura, Chihiro; Sanbo, Makoto; Hirabayashi, Masumi; Nakauchi, Hiromitsu

    2012-11-01

    Recent discovery of a method for derivation and culture of germline-competent rat pluripotent stem cells (PSCs) enables generation of transgenic rats or knock-out rats via genetic modification of such PSCs. This opens the way to use rats, as is routine in mice, for analyses of gene functions or physiological features. In mouse or human, one widely used technique to express a gene of interest stably and ubiquitously is to insert that gene into the Rosa26 locus via gene targeting of PSCs. Rosa26 knock-in mice conditionally expressing a reporter or a toxin gene have contributed to tracing or ablation of specific cell lineages. We successfully identified a rat orthologue of the mouse Rosa26 locus. Insertion of tdTomato, a variant of red fluorescent protein, into the Rosa26 locus of PSCs of various rat strains allows ubiquitous expression of tdTomato. Through germline transmission of one Rosa26-tdTomato knock-in embryonic stem cell line, we also obtained tdTomato knock-in rats. These expressed tdTomato ubiquitously throughout their bodies, which indicates that the rat Rosa26 locus conserves functions of its orthologues in mouse and human. The new tools described here (targeting vectors, knock-in PSCs, and rats) should be useful for a variety of research using rats.

  7. DNA modification study of major depressive disorder: beyond locus-by-locus comparisons.

    Science.gov (United States)

    Oh, Gabriel; Wang, Sun-Chong; Pal, Mrinal; Chen, Zheng Fei; Khare, Tarang; Tochigi, Mamoru; Ng, Catherine; Yang, Yeqing A; Kwan, Andrew; Kaminsky, Zachary A; Mill, Jonathan; Gunasinghe, Cerisse; Tackett, Jennifer L; Gottesman, Irving I; Willemsen, Gonneke; de Geus, Eco J C; Vink, Jacqueline M; Slagboom, P Eline; Wray, Naomi R; Heath, Andrew C; Montgomery, Grant W; Turecki, Gustavo; Martin, Nicholas G; Boomsma, Dorret I; McGuffin, Peter; Kustra, Rafal; Petronis, Art

    2015-02-01

    Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined. We performed DNA modification analysis in white blood cells from monozygotic twins discordant for MDD, in brain prefrontal cortex, and germline (sperm) samples from affected individuals and control subjects (total N = 304) using 8.1K CpG island microarrays and fine mapping. In addition to the traditional locus-by-locus comparisons, we explored the potential of new analytical approaches in epigenomic studies. In the microarray experiment, we detected a number of nominally significant DNA modification differences in MDD and validated selected targets using bisulfite pyrosequencing. Some MDD epigenetic changes, however, overlapped across brain, blood, and sperm more often than expected by chance. We also demonstrated that stratification for disease severity and age may increase the statistical power of epimutation detection. Finally, a series of new analytical approaches, such as DNA modification networks and machine-learning algorithms using binary and quantitative depression phenotypes, provided additional insights on the epigenetic contributions to MDD. Mapping epigenetic differences in MDD (and other psychiatric diseases) is a complex task. However, combining traditional and innovative analytical strategies may lead to identification of disease-specific etiopathogenic epimutations. Copyright © 2015 Society of Biological Psychiatry. All rights reserved.

  8. Structure, function, and phylogeny of the mating locus in the Rhizopus oryzae complex.

    Directory of Open Access Journals (Sweden)

    Andrii P Gryganskyi

    2010-12-01

    Full Text Available The Rhizopus oryzae species complex is a group of zygomycete fungi that are common, cosmopolitan saprotrophs. Some strains are used beneficially for production of Asian fermented foods but they can also act as opportunistic human pathogens. Although R. oryzae reportedly has a heterothallic (+/- mating system, most strains have not been observed to undergo sexual reproduction and the genetic structure of its mating locus has not been characterized. Here we report on the mating behavior and genetic structure of the mating locus for 54 isolates of the R. oryzae complex. All 54 strains have a mating locus similar in overall organization to Phycomyces blakesleeanus and Mucor circinelloides (Mucoromycotina, Zygomycota. In all of these fungi, the minus (- allele features the SexM high mobility group (HMG gene flanked by an RNA helicase gene and a TP transporter gene (TPT. Within the R. oryzae complex, the plus (+ mating allele includes an inserted region that codes for a BTB/POZ domain gene and the SexP HMG gene. Phylogenetic analyses of multiple genes, including the mating loci (HMG, TPT, RNA helicase, ITS1-5.8S-ITS2 rDNA, RPB2, and LDH genes, identified two distinct groups of strains. These correspond to previously described sibling species R. oryzae sensu stricto and R. delemar. Within each species, discordant gene phylogenies among multiple loci suggest an outcrossing population structure. The hypothesis of random-mating is also supported by a 50:50 ratio of plus and minus mating types in both cryptic species. When crossed with tester strains of the opposite mating type, most isolates of R. delemar failed to produce zygospores, while isolates of R. oryzae produced sterile zygospores. In spite of the reluctance of most strains to mate in vitro, the conserved sex locus structure and evidence for outcrossing suggest that a normal sexual cycle occurs in both species.

  9. The Increasing Complexity of the Oncofetal H19 Gene Locus: Functional Dissection and Therapeutic Intervention

    Directory of Open Access Journals (Sweden)

    Abraham Hochberg

    2013-02-01

    Full Text Available The field of the long non-coding RNA (lncRNA is advancing rapidly. Currently, it is one of the most popular fields in the biological and medical sciences. It is becoming increasingly obvious that the majority of the human transcriptome has little or no-protein coding capacity. Historically, H19 was the first imprinted non-coding RNA (ncRNA transcript identified, and the H19/IGF2 locus has served as a paradigm for the study of genomic imprinting since its discovery. In recent years, we have extensively investigated the expression of the H19 gene in a number of human cancers and explored the role of H19 RNA in tumor development. Here, we discuss recently published data from our group and others that provide further support for a central role of H19 RNA in the process of tumorigenesis. Furthermore, we focus on major transcriptional modulators of the H19 gene and discuss them in the context of the tumor-promoting activity of the H19 RNA. Based on the pivotal role of the H19 gene in human cancers, we have developed a DNA-based therapeutic approach for the treatment of cancers that have upregulated levels of H19 expression. This approach uses a diphtheria toxin A (DTA protein expressed under the regulation of the H19 promoter to treat tumors with significant expression of H19 RNA. In this review, we discuss the treatment of four cancer indications in human subjects using this approach, which is currently under development. This represents perhaps one of the very few examples of an existing DNA-based therapy centered on an lncRNA system. Apart from cancer, H19 expression has been reported also in other conditions, syndromes and diseases, where deregulated imprinting at the H19 locus was obvious in some cases and will be summarized below. Moreover, the H19 locus proved to be much more complicated than initially thought. It houses a genomic sequence that can transcribe, yielding various transcriptional outputs, both in sense and antisense directions. The

  10. Beta-defensin genomic copy number is not a modifier locus for cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Burgess Juliana

    2005-12-01

    Full Text Available Abstract Human beta-defensin 2 (DEFB4, also known as DEFB2 or hBD-2 is a salt-sensitive antimicrobial protein that is expressed in lung epithelia. Previous work has shown that it is encoded in a cluster of beta-defensin genes at 8p23.1, which varies in copy number between 2 and 12 in different individuals. We determined the copy number of this locus in 355 patients with cystic fibrosis (CF, and tested for correlation between beta-defensin cluster genomic copy number and lung disease associated with CF. No significant association was found.

  11. Inferring Demographic History Using Two-Locus Statistics.

    Science.gov (United States)

    Ragsdale, Aaron P; Gutenkunst, Ryan N

    2017-06-01

    Population demographic history may be learned from contemporary genetic variation data. Methods based on aggregating the statistics of many single loci into an allele frequency spectrum (AFS) have proven powerful, but such methods ignore potentially informative patterns of linkage disequilibrium (LD) between neighboring loci. To leverage such patterns, we developed a composite-likelihood framework for inferring demographic history from aggregated statistics of pairs of loci. Using this framework, we show that two-locus statistics are more sensitive to demographic history than single-locus statistics such as the AFS. In particular, two-locus statistics escape the notorious confounding of depth and duration of a bottleneck, and they provide a means to estimate effective population size based on the recombination rather than mutation rate. We applied our approach to a Zambian population of Drosophila melanogaster Notably, using both single- and two-locus statistics, we inferred a substantially lower ancestral effective population size than previous works and did not infer a bottleneck history. Together, our results demonstrate the broad potential for two-locus statistics to enable powerful population genetic inference. Copyright © 2017 by the Genetics Society of America.

  12. Fine mapping of the NRG1 Hirschsprung's disease locus.

    Directory of Open Access Journals (Sweden)

    Clara Sze-Man Tang

    Full Text Available The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1. To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552 mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR.

  13. Retroviral vectors encoding ADA regulatory locus control region provide enhanced T-cell-specific transgene expression.

    Science.gov (United States)

    Trinh, Alice T; Ball, Bret G; Weber, Erin; Gallaher, Timothy K; Gluzman-Poltorak, Zoya; Anderson, French; Basile, Lena A

    2009-12-30

    Murine retroviral vectors have been used in several hundred gene therapy clinical trials, but have fallen out of favor for a number of reasons. One issue is that gene expression from viral or internal promoters is highly variable and essentially unregulated. Moreover, with retroviral vectors, gene expression is usually silenced over time. Mammalian genes, in contrast, are characterized by highly regulated, precise levels of expression in both a temporal and a cell-specific manner. To ascertain if recapitulation of endogenous adenosine deaminase (ADA) expression can be achieved in a vector construct we created a new series of Moloney murine leukemia virus (MuLV) based retroviral vector that carry human regulatory elements including combinations of the ADA promoter, the ADA locus control region (LCR), ADA introns and human polyadenylation sequences in a self-inactivating vector backbone. A MuLV-based retroviral vector with a self-inactivating (SIN) backbone, the phosphoglycerate kinase promoter (PGK) and the enhanced green fluorescent protein (eGFP), as a reporter gene, was generated. Subsequent vectors were constructed from this basic vector by deletion or addition of certain elements. The added elements that were assessed are the human ADA promoter, human ADA locus control region (LCR), introns 7, 8, and 11 from the human ADA gene, and human growth hormone polyadenylation signal. Retroviral vector particles were produced by transient three-plasmid transfection of 293T cells. Retroviral vectors encoding eGFP were titered by transducing 293A cells, and then the proportion of GFP-positive cells was determined using fluorescence-activated cell sorting (FACS). Non T-cell and T-cell lines were transduced at a multiplicity of infection (MOI) of 0.1 and the yield of eGFP transgene expression was evaluated by FACS analysis using mean fluorescent intensity (MFI) detection. Vectors that contained the ADA LCR were preferentially expressed in T-cell lines. Further improvements

  14. Retroviral vectors encoding ADA regulatory locus control region provide enhanced T-cell-specific transgene expression

    Science.gov (United States)

    2009-01-01

    Background Murine retroviral vectors have been used in several hundred gene therapy clinical trials, but have fallen out of favor for a number of reasons. One issue is that gene expression from viral or internal promoters is highly variable and essentially unregulated. Moreover, with retroviral vectors, gene expression is usually silenced over time. Mammalian genes, in contrast, are characterized by highly regulated, precise levels of expression in both a temporal and a cell-specific manner. To ascertain if recapitulation of endogenous adenosine deaminase (ADA) expression can be achieved in a vector construct we created a new series of Moloney murine leukemia virus (MuLV) based retroviral vector that carry human regulatory elements including combinations of the ADA promoter, the ADA locus control region (LCR), ADA introns and human polyadenylation sequences in a self-inactivating vector backbone. Methods A MuLV-based retroviral vector with a self-inactivating (SIN) backbone, the phosphoglycerate kinase promoter (PGK) and the enhanced green fluorescent protein (eGFP), as a reporter gene, was generated. Subsequent vectors were constructed from this basic vector by deletion or addition of certain elements. The added elements that were assessed are the human ADA promoter, human ADA locus control region (LCR), introns 7, 8, and 11 from the human ADA gene, and human growth hormone polyadenylation signal. Retroviral vector particles were produced by transient three-plasmid transfection of 293T cells. Retroviral vectors encoding eGFP were titered by transducing 293A cells, and then the proportion of GFP-positive cells was determined using fluorescence-activated cell sorting (FACS). Non T-cell and T-cell lines were transduced at a multiplicity of infection (MOI) of 0.1 and the yield of eGFP transgene expression was evaluated by FACS analysis using mean fluorescent intensity (MFI) detection. Results Vectors that contained the ADA LCR were preferentially expressed in T

  15. Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism.

    Science.gov (United States)

    Buyske, Steven; Williams, Tanishia A; Mars, Audrey E; Stenroos, Edward S; Ming, Sue X; Wang, Rong; Sreenath, Madhura; Factura, Marivic F; Reddy, Chitra; Lambert, George H; Johnson, William G

    2006-02-10

    Certain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus. A likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearson's chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism. Although the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.

  16. Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism

    Directory of Open Access Journals (Sweden)

    Wang Rong

    2006-02-01

    Full Text Available Abstract Background Certain loci on the human genome, such as glutathione S-transferase M1 (GSTM1, do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus. Results A likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearson's chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism. Conclusion Although the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis an association of the homozygous GSTM1 deletion genotype with autism.

  17. Locus-specific view of flax domestication history

    Science.gov (United States)

    Fu, Yong-Bi; Diederichsen, Axel; Allaby, Robin G

    2012-01-01

    Crop domestication has been inferred genetically from neutral markers and increasingly from specific domestication-associated loci. However, some crops are utilized for multiple purposes that may or may not be reflected in a single domestication-associated locus. One such example is cultivated flax (Linum usitatissimum L.), the earliest oil and fiber crop, for which domestication history remains poorly understood. Oil composition of cultivated flax and pale flax (L. bienne Mill.) indicates that the sad2 locus is a candidate domestication locus associated with increased unsaturated fatty acid production in cultivated flax. A phylogenetic analysis of the sad2 locus in 43 pale and 70 cultivated flax accessions established a complex domestication history for flax that has not been observed previously. The analysis supports an early, independent domestication of a primitive flax lineage, in which the loss of seed dispersal through capsular indehiscence was not established, but increased oil content was likely occurred. A subsequent flax domestication process occurred that probably involved multiple domestications and includes lineages that contain oil, fiber, and winter varieties. In agreement with previous studies, oil rather than fiber varieties occupy basal phylogenetic positions. The data support multiple paths of flax domestication for oil-associated traits before selection of the other domestication-associated traits of seed dispersal loss and fiber production. The sad2 locus is less revealing about the origin of winter tolerance. In this case, a single domestication-associated locus is informative about the history of domesticated forms with the associated trait while partially informative on forms less associated with the trait. PMID:22408732

  18. [Observation and analysis on mutation of routine STR locus].

    Science.gov (United States)

    Li, Qiu-yang; Feng, Wei-jun; Yang, Qin-gen

    2005-05-01

    To observe and analyze the characteristic of mutation at STR locus. 27 mutant genes observed in 1211 paternity testing cases were checked by PAGE-silver stained and PowerPlex 16 System Kit and validated by sequencing. Mutant genes locate on 15 loci. The pattern of mutation was accord with stepwise mutation model. The mutation ratio of male-to-female was 8:1 and correlated to the age of father. Mutation rate is correlated to the geometric mean of the number of homogeneous repeats of locus. The higher the mean, the higher the mutation rate. These loci are not so appropriate for use in paternity testing.

  19. Heterotic trait locus (HTL) mapping identifies intra-locus interactions that underlie reproductive hybrid vigor in Sorghum bicolor.

    Science.gov (United States)

    Ben-Israel, Imri; Kilian, Benjamin; Nida, Habte; Fridman, Eyal

    2012-01-01

    Identifying intra-locus interactions underlying heterotic variation among whole-genome hybrids is a key to understanding mechanisms of heterosis and exploiting it for crop and livestock improvement. In this study, we present the development and first use of the heterotic trait locus (HTL) mapping approach to associate specific intra-locus interactions with an overdominant heterotic mode of inheritance in a diallel population using Sorghum bicolor as the model. This method combines the advantages of ample genetic diversity and the possibility of studying non-additive inheritance. Furthermore, this design enables dissecting the latter to identify specific intra-locus interactions. We identified three HTLs (3.5% of loci tested) with synergistic intra-locus effects on overdominant grain yield heterosis in 2 years of field trials. These loci account for 19.0% of the heterotic variation, including a significant interaction found between two of them. Moreover, analysis of one of these loci (hDPW4.1) in a consecutive F2 population confirmed a significant 21% increase in grain yield of heterozygous vs. homozygous plants in this locus. Notably, two of the three HTLs for grain yield are in synteny with previously reported overdominant quantitative trait loci for grain yield in maize. A mechanism for the reproductive heterosis found in this study is suggested, in which grain yield increase is achieved by releasing the compensatory tradeoffs between biomass and reproductive output, and between seed number and weight. These results highlight the power of analyzing a diverse set of inbreds and their hybrids for unraveling hitherto unknown allelic interactions mediating heterosis.

  20. The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology

    Science.gov (United States)

    Mallet, François; Bouton, Olivier; Prudhomme, Sarah; Cheynet, Valérie; Oriol, Guy; Bonnaud, Bertrand; Lucotte, Gérard; Duret, Laurent; Mandrand, Bernard

    2004-01-01

    The definitive demonstration of a role for a recently acquired gene is a difficult task, requiring exhaustive genetic investigations and functional analysis. The situation is indeed much more complicated when facing multicopy gene families, because most or portions of the gene are conserved among the hundred copies of the family. This is the case for the ERVWE1 locus of the human endogenous retrovirus W family (HERV-W), which encodes an envelope glycoprotein (syncytin) likely involved in trophoblast differentiation. Here we describe, in 155 individuals, the positional conservation of this locus and the preservation of the envelope ORF. Sequencing of the critical elements of the ERVWE1 provirus showed a striking conservation among the 48 alleles of 24 individuals, including the LTR elements involved in the transcriptional machinery, the splice sites involved in the maturation of subgenomic Env mRNA, and the Env ORF. The functionality and tissue specificity of the 5′ LTR were demonstrated, as well as the fusogenic activity of the envelope polymorphic variants. Such functions were also shown to be preserved in the orthologous loci isolated from chimpanzee, gorilla, orangutan, and gibbon. This functional preservation among humans and during evolution strongly argued for the involvement of this recently acquired retroviral envelope glycoprotein in hominoid placental physiology. PMID:14757826

  1. HIV control through a single nucleotide on the HLA-B locus

    DEFF Research Database (Denmark)

    Kløverpris, Henrik N; Harndahl, Mikkel; Leslie, Alasdair J

    2012-01-01

    Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and str......Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells......:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C......-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (P = 2 × 10...

  2. Locus of legitimacy and startup resource acquisition strategies: Evidence from social enterprises in South Korea and Taiwan

    Directory of Open Access Journals (Sweden)

    Yi Ling Yang

    2018-05-01

    Full Text Available Purpose - Theoretically, the paper aims to provide locus of legitimacy as a framework to not only introduce a multidimensional perspective on legitimacy but also expand the understanding about resource acquisition strategies of social enterprises. Empirically, the authors test the theoretical predictions by using cases from South Korea and Taiwan. Practically, the authors intend to assist chief executive officers (CEOs of social enterprises in their effort to secure valuable resources and provide policy implications so that both South Korea and Taiwan learn from each other. Design/methodology/approach - The authors use case methods to find evidence of the proposed theoretical framework. The initial search for target companies showed that social enterprises in South Korea and Taiwan were ideal samples. In-person, email and phone interviews were conducted on CEOs, and archival data on institutional environments and various aspects of social enterprises were collected. Collected data were analyzed using the locus of legitimacy framework to find out how different emphasis on locus of legitimacy impacted critical decisions of social enterprise, such as human, financial and network resources. Findings - As predicted in the locus of the legitimacy framework, the analyses confirmed that locus of legitimacy did explain critical decisions of social enterprises in South Korea and Taiwan. First, significant institutional forces existed, shaping social enterprises behavior. For example, Taiwanese Jinu showed that greater emphasis was given to internal legitimacy, while South Korean Sohwa was higher in external locus of legitimacy. Such differences systematically impacted choices made on resource acquisition strategies. Jinu showed a greater similarity to those of for-profit companies, aligning key decisions of resource acquisition strategies to achieve financial viability as a top priority. However, Sohwa, though financial performance was still important

  3. Locus of Control and Technology Adoption in Developing Country Agriculture

    DEFF Research Database (Denmark)

    Abay, Kibrom Araya; Blalock, Garrick; Berhane, Guush

    2017-01-01

    and psychological explanations for the low rates of adoption of profitable agricultural technologies in Sub-Saharan Africa. Our results highlight that improving farmers’ non-cognitive skills (locus of control) may facilitate technology adoption and agricultural transformation. More generally, the results suggest...

  4. AUTOMATIC GENERATION OF ROOT LOCUS PLOTS FOR LINEAR ...

    African Journals Online (AJOL)

    Design and analysis of control systems often become difficult due to the complexity of the system model and the design techniques involved. This paper presents the development of a Tools Box in Microsoft Excel for control engineer that uses root locus as a time domain technique for system design and analysis. The Tool ...

  5. Male-pattern baldness susceptibility locus at 20p11.

    NARCIS (Netherlands)

    Richards, J.B.; Yuan, X.; Geller, F.; Waterworth, D.; Bataille, V.; Glass, D.; Song, K.; Waeber, G.; Vollenweider, P.; Aben, K.K.H.; Kiemeney, L.A.L.M.; Walters, B.; Soranzo, N.; Thorsteinsdottir, U.; Kong, A.; Rafnar, T.; Deloukas, P.; Sulem, P.; Stefansson, H.; Stefansson, K.; Spector, T.D.; Mooser, V.

    2008-01-01

    We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both

  6. (PLWHA): influence of social support, self-esteem, health locus

    African Journals Online (AJOL)

    Coping among people living with HIV/AIDS (PLWHA): influence of social support, self-esteem, health locus of control and gender. ... approach, social support should be in the front burner, society should be sensitized to the importance of social support that is culturally appropriate and behaviour modification focused.

  7. Relationship Among Achievement Motivation, Self-Esteem, Locus of ...

    African Journals Online (AJOL)

    The thrust of the study was to examine the relationship among achievement motivation, self-esteem, locus of control and academic performance of university students in a Nigerian University. The purpose was to determine the extent university student\\'s academic performance was influenced by these criterion variables.

  8. Locus of control and learning strategies as predictors of academic ...

    African Journals Online (AJOL)

    The aim of the research was to determine the relationships which exist between academic success, learning strategies and locus of control. In order to achieve this aim a small-scale quantitative study, utilising two inventories, was done. The first measuring instrument is the Learning and Study Strategies Inventory, which is ...

  9. Y-Chromosome short tandem repeat, typing technology, locus ...

    African Journals Online (AJOL)

    Aghomotsegin

    2015-07-08

    Jul 8, 2015 ... Y-Chromosome short tandem repeat, typing technology, locus information and allele frequency in different population: A review. Muhanned Abdulhasan Kareem1, Ameera Omran Hussein2 and Imad Hadi Hameed2*. 1Babylon University, Centre of Environmental Research, Hilla City, Iraq. 2Department of ...

  10. Influence of Locus Control on Real and Perceived Relationships ...

    African Journals Online (AJOL)

    They included the Nowicki-Strickland Internal – External Locus of Control Scale for children by Nowicki and Strickland (1973) and Emotional – Social Loneliness Inventory by Vincenzi and Grabosky, (1987). A cross sectional survey design was used while regression analysis and multivariate statistics were used in data ...

  11. Screening for genomic rearrangements at BRCA1 locus in Iranian ...

    Indian Academy of Sciences (India)

    2016-08-26

    Aug 26, 2016 ... Home; Journals; Journal of Genetics; Volume 92; Issue 1. Screening for genomic rearrangements at BRCA1 locus in Iranian women with breast cancer using multiplex ligation-dependent probe amplification. Vahid R. Yassaee Babak Emamalizadeh Mir Davood Omrani. Research Note Volume 92 Issue 1 ...

  12. Gender, Age and Locus of Control as Correlates of Remedial ...

    African Journals Online (AJOL)

    Gender, Age and Locus of Control as Correlates of Remedial Learners' Attitude towards English Language. ... These findings have far-reaching implications for adult and non-formal education practitioners and other stakeholders interested in improving the lots of several learners out there, in English language. Keywords: ...

  13. Sex Differences in Locus of Control, Helplessness, Hopelessness, and Depression.

    Science.gov (United States)

    Kolotkin, Richard A.; And Others

    This experiment investigated: (1) relationships among locus of control, attributional style, and depression; (2) if a depressogenic attributional style could be empirically isolated; and (3) if reliable relationships existed between attribution and depression when depression was operationalized using different instruments. Subjects completed the…

  14. Demographic Determinants of Locus of Control among Medical ...

    African Journals Online (AJOL)

    The Levenson Multidimensional Locus of Control Inventory and a Socio - demographic data collection sheet were used to collect data from 262 (183 males and 79 females) students selected through convenience sampling. Data were th analyzed using the 16th version of the SPPS. Percentages, means, t-test and ANOVA ...

  15. Single locus complementary sex determination in Hymenoptera : an "unintelligent" design?

    NARCIS (Netherlands)

    Wilgenburg, Ellen van; Driessen, Gerard; Beukeboom, Leo W.

    2006-01-01

    The haplodiploid sex determining mechanism in Hymenoptera (males are haploid, females are diploid) has played an important role in the evolution of this insect order. In Hymenoptera sex is usually determined by a single locus, heterozygotes are female and hemizygotes are male. Under inbreeding,

  16. Single locus complementary sex determination in Hymenoptera: an "unintelligent" design?

    NARCIS (Netherlands)

    van Wilgenburg, E.; Driessen, G.J.J.; Beukeboom, L.W.

    2006-01-01

    The haplodiploid sex determining mechanism in Hymenoptera (males are haploid, females are diploid) has played an important role in the evolution of this insect order. In Hymenoptera sex is usually determined by a single locus, heterozygotes are female and hemizygotes are male. Under inbreeding,

  17. The Influence of Locus of Control on Student Financial Behavior

    Science.gov (United States)

    Britt, Sonya; Cumbie, Julie A.; Bell, Mary M.

    2013-01-01

    Data on psychological influences of financial behaviors has not been well addressed in student populations, which is concerning given the high levels of general and financial stress experienced by college students. The findings of this study indicate that college students with an external locus of control exhibit the worst financial behaviors.…

  18. Dealing with Malfunction: Locus of Control in Web-Conferencing

    Science.gov (United States)

    Klebl, Michael

    2014-01-01

    This paper considers how students deal with malfunctions that occur during the use of web conferencing systems in learning arrangements. In a survey among participants in online courses that make use of a web-conferencing system (N = 129), the relationship between a preference for internal or external locus of control and the perception of…

  19. Influences of peer relations and locus of control on students ...

    African Journals Online (AJOL)

    Effort to checkmate extravagance and maximize gain is the focus of all organizations more in this period of global financial crisis. There is need therefore to checkmate unnecessary financial spending. This study examines the influence of the variables, peer relations and locus of control, on such spending among University ...

  20. Exploring Learner Autonomy: Language Learning Locus of Control in Multilinguals

    Science.gov (United States)

    Peek, Ron

    2016-01-01

    By using data from an online language learning beliefs survey (n?=?841), defining language learning experience in terms of participants' multilingualism, and using a domain-specific language learning locus of control (LLLOC) instrument, this article examines whether more experienced language learners can also be seen as more autonomous language…

  1. A multi-locus phylogenetic evaluation of Diaporthe (Phomopsis)

    NARCIS (Netherlands)

    Udayanga, D.; Liu, X.; Crous, P.W.; McKenzie, E.H.C.; Chukeatirote, E.; Hyde, K.D.

    2012-01-01

    The genus Diaporthe (Phomopsis) includes important plant pathogenic fungi with wide host ranges and geographic distributions. In the present study, phylogenetic species recognition in Diaporthe is re-evaluated using a multi-locus phylogeny based on a combined data matrix of rDNA ITS, and partial

  2. Relationship between internet addiction and academic locus of ...

    African Journals Online (AJOL)

    The study identified the various internet activities engaged in by students in a Nigerian University and examined the relationship between internet addiction and their academic locus of control. The sample was made of 250 students selected from a University in Nigeria. An instrument tagged “Questionnaire on Students' ...

  3. Arousal, exploration and the locus coeruleus-norepinephrine system

    NARCIS (Netherlands)

    Jepma, Marieke

    2011-01-01

    The studies described in this thesis address a range of topics related to arousal, exploration, temporal attention, and the locus coeruleus-norepinephrine (LC-NE) system. Chapters 2 and 3 report two studies that investigated a recent theory about the role of the LC-NE system in the regulation of the

  4. Locus of Control and Likelihood of Nuclear War: Two Studies.

    Science.gov (United States)

    Erdahl, Paul; Rounds, James B.

    The Nuclear Locus of Control (NLOC) scales were constructed to assess beliefs as to whether nuclear war and nuclear policy decisions are, or can be, influenced by oneself, powerful others, or chance. Three scales measuring internal, powerful others, and chance nuclear LOC show internal consistency estimates (Cronbach's Alpha) of .87, .76, and .85,…

  5. Should Farmers' Locus of Control Be Used in Extension?

    Science.gov (United States)

    Nuthall, Peter L.

    2010-01-01

    To explore whether Farmers' Locus of Control (LOC) could be useful in agricultural extension programmes to improve managerial ability. This test records a farmer's belief in her/his control over production outcomes. A mail survey of 2300 New Zealand farmers was used to obtain a range of variables, and to measure their LOC using a question set…

  6. DNA marker mining of ILSTS035 microsatellite locus on ...

    Indian Academy of Sciences (India)

    Unknown

    We describe tests for detecting and locating quantitative trait loci (QTL) for traits in Hanwoo cattle. From results of a permutation test to detect QTL for marbling, we selected the microsatellite locus ILSTS035 on chromosome 6 for further analysis. K-means clustering analysis applied to five traits and nine DNA markers in ...

  7. Determination of the yield locus by means of temperature measurement

    NARCIS (Netherlands)

    Banabic, D.; Huetink, Han

    2006-01-01

    The paper presents a theoretical background of the thermo-graphical method of determining the yield locus. The analytical expression of the temperature variation of the specimen deformed in the elastic state is determined starting from the first law of thermodynamics. The experimental method for

  8. Inferring relationships between pairs of individuals from locus heterozygosities

    Directory of Open Access Journals (Sweden)

    Spinetti Isabella

    2002-11-01

    Full Text Available Abstract Background The traditional exact method for inferring relationships between individuals from genetic data is not easily applicable in all situations that may be encountered in several fields of applied genetics. This study describes an approach that gives affordable results and is easily applicable; it is based on the probabilities that two individuals share 0, 1 or both alleles at a locus identical by state. Results We show that these probabilities (zi depend on locus heterozygosity (H, and are scarcely affected by variation of the distribution of allele frequencies. This allows us to obtain empirical curves relating zi's to H for a series of common relationships, so that the likelihood ratio of a pair of relationships between any two individuals, given their genotypes at a locus, is a function of a single parameter, H. Application to large samples of mother-child and full-sib pairs shows that the statistical power of this method to infer the correct relationship is not much lower than the exact method. Analysis of a large database of STR data proves that locus heterozygosity does not vary significantly among Caucasian populations, apart from special cases, so that the likelihood ratio of the more common relationships between pairs of individuals may be obtained by looking at tabulated zi values. Conclusions A simple method is provided, which may be used by any scientist with the help of a calculator or a spreadsheet to compute the likelihood ratios of common alternative relationships between pairs of individuals.

  9. Response to selection in finite locus models with nonadditive effects

    NARCIS (Netherlands)

    Esfandyari, Hadi; Henryon, Mark; Berg, Peer; Thomasen, Jørn Rind; Bijma, Piter; Sørensen, Anders Christian

    2017-01-01

    Under the finite-locus model in the absence of mutation, the additive genetic variation is expected to decrease when directional selection is acting on a population, according to quantitative-genetic theory. However, some theoretical studies of selection suggest that the level of additive

  10. Locus of control and investment in risky assets

    NARCIS (Netherlands)

    Salamanca Acosta, Nicolas; de Grip, A.; Fouarge, Didier; Montizaan, Raymond

    2016-01-01

    We show that household heads with a strong internal economic locus of control are more likely to hold equity and hold a larger share of equity in their investment portfolio. This relation holds when we control for economic preferences and possible confounders such as financial literacy,

  11. 40 CFR 798.5195 - Mouse biochemical specific locus test.

    Science.gov (United States)

    2010-07-01

    ...-induced variants are bred to determine the genetic nature of the change. (f) Data and reports—(1... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5195 Mouse...) A biochemical specific locus mutation is a genetic change resulting from a DNA lesion causing...

  12. Emotional intelligence and locus of control of adult patients with ...

    African Journals Online (AJOL)

    Background: This article investigates emotional intelligence and locus of control in an adult breast cancer population receiving treatment. Gaining insight into these constructs will contribute to improving breast cancer patients' psychological well-being and to reducing physical vulnerability to disease before and during ...

  13. The Locus of Metaphorical Persuasion: An Empirical Test.

    Science.gov (United States)

    Hitchon, Jacqueline C.

    1997-01-01

    Investigates whether the locus of persuasion of the metaphor "A is B" lies in the valence of B, as widely assumed, or in the valence of the metaphor ground, what A and B share. Indicates that global affect toward B does not transfer onto A and that metaphorical persuasion is a distinct process meriting further investigation. (SR)

  14. Social support, locus of control, and psychological well-being

    NARCIS (Netherlands)

    van der Zee, KI; Buunk, BP; Sanderman, R

    1997-01-01

    Social support seems to be positively related to psychological well-being. Studies have shown that individual differences exist in the ability to mobilize and use sources of support. The current study focused on locus of control as a personality factor that might be related to this ability, In 2

  15. Locus of Control and Neuropsychological Performance in Chronic Alcoholics.

    Science.gov (United States)

    Shelton, M. D.; And Others

    1982-01-01

    Examined correlated neuropsychological performance in male chronic alcoholics and non-alcoholic controls. Results showed external locus of control (LOC-E) scores to predict performance on neuropsychological tests in alcoholics but not in controls. Suggests the LOC-E variables cannot account for the widespread differences between the groups on…

  16. New distal marker closely linked to the fragile X locus

    NARCIS (Netherlands)

    Hulsebos, T. J.; Oostra, B. A.; Broersen, S.; Smits, A.; van Oost, B. A.; Westerveld, A.

    1991-01-01

    We have isolated II-10, a new X-chromosomal probe that identifies a highly informative two-allele TaqI restriction fragment length polymorphism at locus DXS466. Using somatic cell hybrids containing distinct portions of the long arm of the X chromosome, we could localize DXS466 between DXS296 and

  17. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

    NARCIS (Netherlands)

    Guigas, B.; Leeuw van Weenen, J.E. de; van Leeuwen, N.; Simonis-Bik, A.M.; Haeften, T.W. van; Nijpels, G.; Houwing-Duistermaat, J.J.; Beekman, M.; Deelen, J.; Havekes, L.M.; Penninx, B.W.J.H.; Vogelzangs, N.; Riet, E. van 't; Dehghan, A.; Hofman, A.; Witteman, J.C.; Uitterlinden, A.G.; Grarup, N.; Jørgensen, T.; Witte, D.R.; Lauritzen, T.; Hansen, T.; Pedersen, O.; Hottenga, J.; Romijn, J.A.; Diamant, M.; Kramer, M.H.H.; Heine, R.J.; Willemsen, G.; Dekker, J.M.; Eekhoff, E.M.; Pijl, H.; Geus, E.J. de; Slagboom, P.E.; Hart, L.M. 't

    2014-01-01

    Aims: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. Methods: Four potentially

  18. DMPD: The Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 10669111 The Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. Qur...e The Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. Authors Qur

  19. [Relationship between work locus of control and occupational stress in oil workers].

    Science.gov (United States)

    Meng, Xian-Hai; He, Ya-Hui; Yu, Shan-Fa; Qi, Xiu-Ying

    2008-12-01

    To investigate general states of the work locus of control and explore the relationship between work locus of control and occupational stress in oil workers. 582 oil workers were investigated by using the General Questionnaire and Occupational Stress Measure Inventory. There were significant differences in WCLS score between two age groups (= 30 years old group and locus of control; values of role ambiguity, working prospect, depression and social support were higher in the group of external locus of control (P locus of control had positive relation with role ambiguity, working prospect, depression, and social support, and negative with interpersonal relationship, promotion, participation, task consistency, challenge, job satisfaction, mental health, self-esteem and coping strategies. In the regression analysis, work locus of control was the major predictive factor of work satisfaction. Work locus of control is associated with many occupational stress factors. The group of extrinsic work locus of control experience more stress in oil workers.

  20. Genetic Dissection of the Canq1 Locus Governing Variation in Extent of the Collateral Circulation

    Science.gov (United States)

    Wang, Shiliang; Zhang, Hua; Wiltshire, Tim; Sealock, Robert; Faber, James E.

    2012-01-01

    Background Native (pre-existing) collaterals are arteriole-to-arteriole anastomoses that interconnect adjacent arterial trees and serve as endogenous bypass vessels that limit tissue injury in ischemic stroke, myocardial infarction, coronary and peripheral artery disease. Their extent (number and diameter) varies widely among mouse strains and healthy humans. We previously identified a major quantitative trait locus on chromosome 7 (Canq1, LOD = 29) responsible for 37% of the heritable variation in collateral extent between C57BL/6 and BALB/c mice. We sought to identify candidate genes in Canq1 responsible for collateral variation in the cerebral pial circulation, a tissue whose strain-dependent variation is shared by similar variation in other tissues. Methods and Findings Collateral extent was intermediate in a recombinant inbred line that splits Canq1 between the C57BL/6 and BALB/c strains. Phenotyping and SNP-mapping of an expanded panel of twenty-one informative inbred strains narrowed the Canq1 locus, and genome-wide linkage analysis of a SWRxSJL-F2 cross confirmed its haplotype structure. Collateral extent, infarct volume after cerebral artery occlusion, bleeding time, and re-bleeding time did not differ in knockout mice for two vascular-related genes located in Canq1, IL4ra and Itgal. Transcript abundance of 6 out of 116 genes within the 95% confidence interval of Canq1 were differentially expressed >2-fold (p-valuecollateral formation. Conclusions These findings refine the Canq1 locus and identify several genes as high-priority candidates important in specifying native collateral formation and its wide variation. PMID:22412848

  1. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Guigas, B; de Leeuw van Weenen, J E; van Leeuwen, N

    2014-01-01

    AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. METHODS: Four potentially....... In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated...

  2. Loss of hMSH2 gene expression correlates with improved survival in ...

    Indian Academy of Sciences (India)

    1Department of General and Colorectal Surgery, Medical University of Lodz, pl. Hallera 1 ... expression and clinical parameters but our studies showed ... Journal of Genetics, Vol. .... cancer, further investigation of genetic alterations caused by.

  3. The aesthetic imaginary as an anthropological locus. Thinking an Anthropology based on Imaginary.

    Directory of Open Access Journals (Sweden)

    Patricia María Calvo

    2015-04-01

    Full Text Available The process by which man is capable of creating beauty not only gives us a fruitive experience but also knowledge of our human nature. Therefore we intend to understand what epistemological possibilities a work of art opens and, ultimately, what we know of man through it and why. Out of an interdisciplinary and dialogical perspective, projected by authors as Adolphe Gesché and Hans-Georg Gadamer, among others, we propose that the imaginary world opened and established by art becomes a privileged locus for human knowledge. The imagery is the symbolic area built by the artists and the community, which influences and affects every member of it, and where the community builds its identity known.Key Words: Imaginary, aesthetics, poiésis, anthropology.

  4. Relationship of locus of control with plaque and gingival status before and after oral health education in a group of college students - an experimental study.

    Science.gov (United States)

    Potdar, S; Lakshminarayan, N; Goud Reddy, S

    2015-02-01

    In health psychology, several models are being constructed to understand human behaviour. Multidimensional health locus of control (MHLC) is one among them. We sought to know the relationship of MHLC with dental plaque and gingival status before and after oral health education programme among 286 college students, aged 18-21 years in Davangere city. Multidimensional health locus of control questionnaire consisting of questions measuring internal health locus of control (IHLC), powerful others health locus of control (PHLC) and chance health locus of control (CHLC) was administered to students. Dental plaque and gingival health status were recorded using Plaque Index (PLI) and Gingival Index (GI), 1967. Oral health education was provided using power point presentation after the baseline oral examination. After 10 weeks of intervention, the students were given the same proforma followed by the assessment of plaque and gingival status. A negative correlation was observed between PHLC and IHLC with PLI and GI and positive correlation of CHLC with PLI and GI at a level of P education was found to be effective and this could change the behaviour of individuals. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. A cut locus for finite graphs and the farthest point mapping

    DEFF Research Database (Denmark)

    Maddaloni, Alessandro; Zamfirescu, Carol T.

    2016-01-01

    We reflect upon an analogue of the cut locus, a notion classically studied in Differential Geometry, for finite graphs. The cut locus C(x) of a vertex x shall be the graph induced by the set of all vertices y with the property that no shortest path between x and z, z≠y, contains y. The cut locus ...

  6. Reframing Student Affairs Leadership: An Analysis of Organizational Frames of Reference and Locus of Control

    Science.gov (United States)

    Tull, Ashley; Freeman, Jerrid P.

    2011-01-01

    Examined in this study were the identified frames of reference and locus of control used by 478 student affairs administrators. Administrator responses were examined to identify frames of reference most commonly used and their preference order. Locus of control most commonly used and the relationship between frames of reference and locus of…

  7. Locus of Control in Offenders and Alleged Offenders with Learning Disabilities

    Science.gov (United States)

    Goodman, Wendy; Leggett, Janice; Garrett, Tanya

    2007-01-01

    Locus of control can be a useful measure of treatment outcome in offenders from the general population. However, there is little information regarding locus of control and offenders with learning disabilities. Existing measures of locus of control use complex language and abstract ideas that may not be accessible to individuals in this group. A…

  8. Rasch Analysis of the Locus-of-Hope Scale. Brief Report

    Science.gov (United States)

    Gadiana, Leny G.; David, Adonis P.

    2015-01-01

    The Locus-of-Hope Scale (LHS) was developed as a measure of the locus-of-hope dimensions (Bernardo, 2010). The present study adds to the emerging literature on locus-of-hope by assessing the psychometric properties of the LHS using Rasch analysis. The results from the Rasch analyses of the four subscales of LHS provided evidence on the…

  9. On the Relation of Locus of Control and L2 Reading and Writing Achievement

    Science.gov (United States)

    Ghonsooly, Behzad; Shirvan, Majid Elahi

    2011-01-01

    Locus of control, a psychological construct, has been the focus of attention in recent decades. Psychologists have discussed the effect of locus of control on achieving life goals in social/psychological interactions. While learning a foreign language involves both social interactions and psychological processes, the role and relation of locus of…

  10. Characterization of a Multipeptide Lantibiotic Locus in Streptococcus pneumoniae.

    Science.gov (United States)

    Maricic, Natalie; Anderson, Erica S; Opipari, AnneMarie E; Yu, Emily A; Dawid, Suzanne

    2016-01-26

    Bacterial communities are established through a combination of cooperative and antagonistic interactions between the inhabitants. Competitive interactions often involve the production of antimicrobial substances, including bacteriocins, which are small antimicrobial peptides that target other community members. Despite the nearly ubiquitous presence of bacteriocin-encoding loci, inhibitory activity has been attributed to only a small fraction of gene clusters. In this study, we characterized a novel locus (the pld locus) in the pathogen Streptococcus pneumoniae that drives the production of a bacteriocin called pneumolancidin, which has broad antimicrobial activity. The locus encodes an unusual tandem array of four inhibitory peptides, three of which are absolutely required for antibacterial activity. The three peptide sequences are similar but appear to play distinct roles in regulation and inhibition. A modification enzyme typically found in loci encoding a class of highly modified bacteriocins called lantibiotics was required for inhibitory activity. The production of pneumolancidin is controlled by a two-component regulatory system that is activated by the accumulation of modified peptides. The locus is located on a mobile element that has been found in many pneumococcal lineages, although not all elements carry the pld genes. Intriguingly, a minimal region containing only the genes required for pneumolancidin immunity was found in several Streptococcus mitis strains. The pneumolancidin-producing strain can inhibit nearly all pneumococci tested to date and provided a competitive advantage in vivo. These peptides not only represent a unique strategy for bacterial competition but also are an important resource to guide the development of new antimicrobials. Successful colonization of a polymicrobial host surface is a prerequisite for the subsequent development of disease for many bacterial pathogens. Bacterial factors that directly inhibit the growth of neighbors

  11. Role of the sar locus of Staphylococcus aureus in induction of endocarditis in rabbits.

    Science.gov (United States)

    Cheung, A L; Yeaman, M R; Sullam, P M; Witt, M D; Bayer, A S

    1994-05-01

    A regulatory locus on the Staphylococcus aureus chromosome, designated sar, is involved in the expression of cell wall proteins, some of which are potentially important in the pathogenesis of endocarditis. For instance, mutant 11D2 (sar::Tn917LTV1) was found to bind substantially less to matrix proteins (i.e., fibrinogen and fibronectin) than parent strain DB. Remarkably, these two strains did not differ in other phenotypes considered important in the initiation of endocarditis (e.g., binding to platelets and resistance to platelet-derived microbicidal proteins). The isogenic pair were compared for pathogenicity in a rabbit endocarditis model. There were significant differences in infectivity rates between the two strains (71 and 88% for DB versus 17 and 42% for mutant 11D2 at inocula of 10(3) and 10(4) CFU, respectively). In early adherence studies, parent DB adhered substantially better than the mutant to valvular vegetations at an inoculum of 10(6) CFU (P = 0.05). Southern blot analysis of colonies indicated that the location of the Tn917LTV1 insert in mutant 11D2 remained stable after animal passage. In vitro adherence assays revealed that mutant 11D2 was less adherent to cultured human endothelium than parent DB. These studies suggest that the sar locus is involved in the initial adherence of S. aureus to the fibrin-platelet-endothelium matrix on damaged valvular endothelium.

  12. A multi locus variable number of tandem repeat analysis (MLVA scheme for Streptococcus agalactiae genotyping

    Directory of Open Access Journals (Sweden)

    Mereghetti Laurent

    2011-07-01

    Full Text Available Abstract Background Multilocus sequence typing (MLST is currently the reference method for genotyping Streptococcus agalactiae strains, the leading cause of infectious disease in newborns and a major cause of disease in immunocompromised children and adults. We describe here a genotyping method based on multiple locus variable number of tandem repeat (VNTR analysis (MLVA applied to a population of S. agalactiae strains of various origins characterized by MLST and serotyping. Results We studied a collection of 186 strains isolated from humans and cattle and three reference strains (A909, NEM316 and 2603 V/R. Among 34 VNTRs, 6 polymorphic VNTRs loci were selected for use in genotyping of the bacterial population. The MLVA profile consists of a series of allele numbers, corresponding to the number of repeats at each VNTR locus. 98 MLVA genotypes were obtained compared to 51 sequences types generated by MLST. The MLVA scheme generated clusters which corresponded well to the main clonal complexes obtained by MLST. However it provided a higher discriminatory power. The diversity index obtained with MLVA was 0.960 compared to 0.881 with MLST for this population of strains. Conclusions The MLVA scheme proposed here is a rapid, cheap and easy genotyping method generating results suitable for exchange and comparison between different laboratories and for the epidemiologic surveillance of S. agalactiae and analyses of outbreaks.

  13. Haplotype frequencies at the DRD2 locus in populations of the East European Plain

    Directory of Open Access Journals (Sweden)

    Mikulich Alexey I

    2009-09-01

    Full Text Available Abstract Background It was demonstrated previously that the three-locus RFLP haplotype, TaqI B-TaqI D-TaqI A (B-D-A, at the DRD2 locus constitutes a powerful genetic marker and probably reflects the most ancient dispersal of anatomically modern humans. Results We investigated TaqI B, BclI, MboI, TaqI D, and TaqI A RFLPs in 17 contemporary populations of the East European Plain and Siberia. Most of these populations belong to the Indo-European or Uralic language families. We identified three common haplotypes, which occurred in more than 90% of chromosomes investigated. The frequencies of the haplotypes differed according to linguistic and geographical affiliation. Conclusion Populations in the northwestern (Byelorussians from Mjadel', northern (Russians from Mezen' and Oshevensk, and eastern (Russians from Puchezh parts of the East European Plain had relatively high frequencies of haplotype B2-D2-A2, which may reflect admixture with Uralic-speaking populations that inhabited all of these regions in the Early Middle Ages.

  14. Refined localization of the Prieto-syndrome locus

    Energy Technology Data Exchange (ETDEWEB)

    Martinez, F.; Prieto, F. [Unidad de Genetica, Valencia (Spain); Gal, A. [Universitaets-Krankenhaus Eppendorf, Hamburg (Germany)

    1996-07-12

    PRS designates the locus for a syndromal form of X-linked mental retardation (Prieto syndrome) characterized by minor facial anomalies, ear malformation, abnormal growth of teeth, clinodactyly, sacral dimple, patellar luxation, malformation of lower limbs, abnormalities of the fundus of the eye, and subcortical cerebral atrophy. Linkage analysis localized the disease locus between DXS84 (Xp21.1) and DXS255. Here we present additional linkage data that provide further support and refinement of this localization. Individual III-18 gave birth to a male, currently aged 2 7/12 years, who clearly shows delayed psychomotor development. He began to walk at 23 months and his speech is delayed. In addition, he shows the characteristic facial anomalies, {open_quotes}dysplastic{close_quotes} ears, sacral dimple, and clinodactyly, as do all other affected males in this family. 7 refs., 1 tab.

  15. Characterization of a Multipeptide Lantibiotic Locus in Streptococcus pneumoniae

    Directory of Open Access Journals (Sweden)

    Natalie Maricic

    2016-01-01

    Full Text Available Bacterial communities are established through a combination of cooperative and antagonistic interactions between the inhabitants. Competitive interactions often involve the production of antimicrobial substances, including bacteriocins, which are small antimicrobial peptides that target other community members. Despite the nearly ubiquitous presence of bacteriocin-encoding loci, inhibitory activity has been attributed to only a small fraction of gene clusters. In this study, we characterized a novel locus (the pld locus in the pathogen Streptococcus pneumoniae that drives the production of a bacteriocin called pneumolancidin, which has broad antimicrobial activity. The locus encodes an unusual tandem array of four inhibitory peptides, three of which are absolutely required for antibacterial activity. The three peptide sequences are similar but appear to play distinct roles in regulation and inhibition. A modification enzyme typically found in loci encoding a class of highly modified bacteriocins called lantibiotics was required for inhibitory activity. The production of pneumolancidin is controlled by a two-component regulatory system that is activated by the accumulation of modified peptides. The locus is located on a mobile element that has been found in many pneumococcal lineages, although not all elements carry the pld genes. Intriguingly, a minimal region containing only the genes required for pneumolancidin immunity was found in several Streptococcus mitis strains. The pneumolancidin-producing strain can inhibit nearly all pneumococci tested to date and provided a competitive advantage in vivo. These peptides not only represent a unique strategy for bacterial competition but also are an important resource to guide the development of new antimicrobials.

  16. 'Locus of control', health-related quality of life, emotional distress and disability in Parkinson's disease.

    Science.gov (United States)

    Rizza, Federica; Gison, Annalisa; Bonassi, Stefano; Dall'Armi, Valentina; Tonto, Francesca; Giaquinto, Salvatore

    2017-06-01

    This cross-sectional study evaluated locus of control and its subscales in Parkinson's disease. A total of 50 consecutive Parkinson's disease participants and 50 healthy volunteers (control group) were enrolled. External locus of control was significantly higher in Parkinson's disease participants, whereas internal locus of control had no significant differences. External locus of control and internal locus of control were correlated in control group, but not in Parkinson's disease. In Parkinson's disease participants, external locus of control was negatively associated with health-related quality of life as well as positively associated with emotional distress and disease severity (but not with disability). After adjusting to confound variables, the associations remained. On the other hand, internal locus of control was negatively associated with depression.

  17. The Effects of Locus of Control and Task Difficulty on Procrastination.

    Science.gov (United States)

    Janssen, Tracy; Carton, John S

    1999-12-01

    The authors investigated the effects of locus of control expectancies and task difficulty on procrastination. Forty-two college students were administered an academic locus of control scale and a task that was similar to a typical college homework assignment. The students were randomly assigned to 1 of 2 task difficulty levels. Although none of the results involving task difficulty was significant, several results involving locus of control were significant. Specifically, analyses revealed that students with internal locus of control expectancies tended to begin working on the assignment sooner than students with external locus of control expectancies. In addition, students with internal locus of control completed and returned the assignment sooner than students with external locus of control. The results are discussed within the context of J. B. Rotter's (1966, 1975, 1982) social learning theory.

  18. Genetic analysis of the claret locus of Drosophila melanogaster

    International Nuclear Information System (INIS)

    Sequeira, W.; Nelson, C.R.; Szauter, P.

    1989-01-01

    The claret (ca) locus of Drosophila melanogaster comprises two separately mutable domains, one responsible for eye color and one responsible for proper disjunction of chromosomes in meiosis and early cleavage divisions. Previously isolated alleles are of three types: (1) alleles of the claret (ca) type that affect eye color only, (2) alleles of the claret-nondisjunctional (ca nd ) type that affect eye color and chromosome behavior, and (3) a meiotic mutation, non-claret disjunctional (ncd), that affects chromosome behavior only. In order to investigate the genetic structure of the claret locus, the authors have isolated 19 radiation-induced alleles of claret on the basis of the eye color phenotype. Two of these 19 new alleles are of the ca nd type, while 17 are of the ca type, demonstrating that the two domains do not often act as a single target for mutagenesis. This suggests that the two separately mutable functions are likely to be encoded by separate or overlapping genes rather than by a single gene. One of the new alleles of the ca nd type is a chromosome rearrangement with a breakpoint at the position of the claret locus. If this breakpoint is the cause of the mutant phenotype and there are no other mutations associated with the rearrangement, the two functions must be encoded by overlapping genes

  19. Population genetics of the HRAS1 minisatellite locus

    Energy Technology Data Exchange (ETDEWEB)

    Devlin, B.; Risch, N. (Yale Univ., New Haven, CT (United States)); Krontiris, T. (Tufts Univ., Boston, MA (United States) New England Medical Center Hospital, Boston, MA (United States))

    1993-12-01

    Several years ago it was reported that rare HRAS1 VNTR alleles occurred more frequently in US Caucasian cancer patients than in unaffected controls. Such an association, in theory, could be caused by undetected population heterogeneity. Also, in a study clearly relevant to this issue, it was recently reported that significant deviations from Hardy-Weinberg equilibrium exist at this locus in a sample of US Caucasians. These considerations motivate population genetic analysis of the HRAS1 locus. From published studies of the HRAS1 VNTR locus, which classified alleles into types, the authors found only small differences in the allele frequency distributions of samples from various European nations, although there were larger differences among ethnic groups (African American, Caucasian, and Oriental). In an analysis of variation of rare-allele frequencies among samples from four European nations, most of the variance was attributable to molecular methodology, and very little of the variance was accounted for by nationality. In addition, the authors showed that mixture of European subpopulations should result in only minor deviations from expected genotype proportions in a Caucasian database and demonstrated that there was no significant deviation from Hardy-Weinberg equilibrium in the HRAS1 data. 35 refs., 4 tabs.

  20. Origin of allelic diversity in antirrhinum S locus RNases.

    Science.gov (United States)

    Xue, Y; Carpenter, R; Dickinson, H G; Coen, E S

    1996-01-01

    In many plant species, self-incompatibility (SI) is genetically controlled by a single multiallelic S locus. Previous analysis of S alleles in the Solanaceae, in which S locus ribonucleases (S RNases) are responsible for stylar expression of SI, has demonstrated that allelic diversity predated speciation within this family. To understand how allelic diversity has evolved, we investigated the molecular basis of gametophytic SI in Antirrhinum, a member of the Scrophulariaceae, which is closely related to the Solanaceae. We have characterized three Antirrhinum cDNAs encoding polypeptides homologous to S RNases and shown that they are encoded by genes at the S locus. RNA in situ hybridization revealed that the Antirrhinum S RNase are primarily expressed in the stylar transmitting tissue. This expression is consistent with their proposed role in arresting the growth of self-pollen tubes. S alleles from the Scrophulariaceae form a separate group from those of the Solanaceae, indicating that new S alleles have been generated since these families separated (approximately 40 million years). We propose that the recruitment of an ancestral RNase gene into SI occurred during an early stage of angiosperm evolution and that, since that time, new alleles subsequently have arisen at a low rate. PMID:8672882

  1. Ornithine aminotransferase (OAT): recombination between an X-linked OAT sequence (7.5 kb) and the Norrie disease locus.

    Science.gov (United States)

    Ngo, J T; Bateman, J B; Spence, M A; Cortessis, V; Sparkes, R S; Kivlin, J D; Mohandas, T; Inana, G

    1990-01-01

    A human ornithine aminotransferase (OAT) locus has been mapped to the Xp11.2, as has the Norrie disease locus. We used a cDNA probe to investigate a 3-generation UCLA family with Norrie disease; a 4.2-kb RFLP was detected and a maximum lod score of 0.602 at zero recombination fraction was calculated. We used the same probe to study a second multigeneration family with Norrie disease from Utah. A different RFLP of 7.5 kb in size was identified and a recombinational event between the OAT locus represented by this RFLP and the disease loci was observed. Linkage analysis of these two loci in this family revealed a maximum load score of 1.88 at a recombination fraction of 0.10. Although both families have affected members with the same disease, the lod scores are reported separately because the 4.2- and 7.5-kb RFLPs may represent two different loci for the X-linked OAT.

  2. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.

    Directory of Open Access Journals (Sweden)

    Yi Lu

    2010-05-01

    Full Text Available Central corneal thickness (CCT, one of the most highly heritable human traits (h(2 typically>0.9, is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058. Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1 had an overall meta-analysis p-value for all the individually genotyped samples of 4.6x10(-10. The locus on chromosome 16 was associated with CCT with p = 8.95x10(-11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS, a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.

  3. Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus.

    Directory of Open Access Journals (Sweden)

    Emily Y Smith

    2011-12-01

    Full Text Available The Prader-Willi syndrome (PWS [MIM 17620] and Angelman syndrome (AS [MIM 105830] locus is controlled by a bipartite imprinting center (IC consisting of the PWS-IC and the AS-IC. The most widely accepted model of IC function proposes that the PWS-IC activates gene expression from the paternal allele, while the AS-IC acts to epigenetically inactivate the PWS-IC on the maternal allele, thus silencing the paternally expressed genes. Gene order and imprinting patterns at the PWS/AS locus are well conserved from human to mouse; however, a murine AS-IC has yet to be identified. We investigated a potential regulatory role for transcription from the Snrpn alternative upstream exons in silencing the maternal allele using a murine transgene containing Snrpn and three upstream exons. This transgene displayed appropriate imprinted expression and epigenetic marks, demonstrating the presence of a functional AS-IC. Transcription of the upstream exons from the endogenous locus correlates with imprint establishment in oocytes, and this upstream exon expression pattern was conserved on the transgene. A transgene bearing targeted deletions of each of the three upstream exons exhibited loss of imprinting upon maternal transmission. These results support a model in which transcription from the Snrpn upstream exons directs the maternal imprint at the PWS-IC.

  4. Expression analyses of the genes harbored by the type 2 diabetes and pediatric BMI associated locus on 10q23

    Directory of Open Access Journals (Sweden)

    Zhao Jianhua

    2012-09-01

    Full Text Available Abstract Background There is evidence that one of the key type 2 diabetes (T2D loci identified by GWAS exerts its influence early on in life through its impact on pediatric BMI. This locus on 10q23 harbors three genes, encoding hematopoietically expressed homeobox (HHEX, insulin-degrading enzyme (IDE and kinesin family member 11 (KIF11, respectively. Methods We analyzed the impact of adipogeneis on the mRNA and protein expression levels of these genes in the human adipocyte Simpson-Golabi-Behmel syndrome (SGBS cell line in order to investigate which could be the culprit gene(s in this region of linkage disequilibrium. Results Following activation of differentiation with a PPARγ ligand, we observed ~20% decrease in IDE, ~40% decrease in HHEX and in excess of 80% decrease in KIF11 mRNA levels when comparing the adipocyte and pre-adipocyte states. We also observed decreases in KIF11 and IDE protein levels, but conversely we observed a dramatic increase in HHEX protein levels. Subsequent time course experiments revealed some marked changes in expression as early as three hours after activation of differentiation. Conclusion Our data suggest that the expression of all three genes at this locus are impacted during SGBS adipogenesis and provides insights in to the possible mechanisms of how the genes at this 10q23 locus could influence both adipocyte differentiation and susceptibility to T2D through insulin resistance.

  5. Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma.

    Directory of Open Access Journals (Sweden)

    John Kuchtey

    2011-02-01

    Full Text Available Primary open angle glaucoma (POAG is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.

  6. Locus de Controle e escolha do método anticoncepcional Locus de Control y método anticonceptivo elegido Locus of Control and choice of contraceptive method

    Directory of Open Access Journals (Sweden)

    Aline Salheb Alves

    2007-06-01

    Full Text Available Objetivou-se avaliar a relação entre o Locus de Controle e o tipo de método contraceptivo escolhido. Foi utilizada a Escala Multidimensional de Locus de Controle de Levenson e entrevistadas 191 mulheres. As usuárias de preservativo masculino apresentaram maior Internalidade do que as usuárias de injetável mensal. Quanto ao locus Externalidade Outros Poderosos, as usuárias de implante apresentavam menor externalidade do que as usuárias de preservativo masculino, laqueadura, injetável trimestral e DIU. Considerando-se o locus Externalidade Acaso, as usuárias de implante apresentaram menores escores do que as mulheres que optaram pela laqueadura, injetável trimestral e DIU. Observou-se ainda, menor Externalidade Acaso entre as usuárias de injetável mensal em relação às mulheres que fizeram opção pelo injetável trimestral.El objetivo es validar la relación entre el Locus de Control y el tipo de método anticonceptivo elegido. Fue usada la Escala Multidimensional de Locus de Control de Levenson. Fueron entrevistadas 191 mujeres. Las usuarias de condón masculino presentaron Internalidad más grande que las usuarias de inyectable mensual. Considerado el Locus Externalidad - Otro poderoso, las usuarias de implante presentaron menor externalidad de que las usuarias de condón masculino, laqueadura, inyectable trimestral y DIU. Considerado el Locus Externalidad - Quizá, las usuarias del implante presentaron menores resultados que las mujeres que eligieron por la laqueadura, inyectable trimestral y DIU. Se observo que las mujeres usuarias de inyectable mensual presentaron menor Externalidad - Quizá que las mujeres usuarias de inyectable trimestral.The purpose was to assess the relationship between locus of control and the contraceptive method chosen. It was used the Levenson's Multidimensional Locus of Control Scale and 191 women was interviewed. Users of male condoms presented greater Internality than the monthly contraceptive

  7. Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome.

    Science.gov (United States)

    Du, Meijun; Yuan, Tiezheng; Schilter, Kala F; Dittmar, Rachel L; Mackinnon, Alexander; Huang, Xiaoyi; Tschannen, Michael; Worthey, Elizabeth; Jacob, Howard; Xia, Shu; Gao, Jianzhong; Tillmans, Lori; Lu, Yan; Liu, Pengyuan; Thibodeau, Stephen N; Wang, Liang

    2015-01-01

    Chromosome 8q24 locus contains regulatory variants that modulate genetic risk to various cancers including prostate cancer (PC). However, the biological mechanism underlying this regulation is not well understood. Here, we developed a chromosome conformation capture (3C)-based multi-target sequencing technology and systematically examined three PC risk regions at the 8q24 locus and their potential regulatory targets across human genome in six cell lines. We observed frequent physical contacts of this risk locus with multiple genomic regions, in particular, inter-chromosomal interaction with CD96 at 3q13 and intra-chromosomal interaction with MYC at 8q24. We identified at least five interaction hot spots within the predicted functional regulatory elements at the 8q24 risk locus. We also found intra-chromosomal interaction genes PVT1, FAM84B and GSDMC and inter-chromosomal interaction gene CXorf36 in most of the six cell lines. Other gene regions appeared to be cell line-specific, such as RRP12 in LNCaP, USP14 in DU-145 and SMIN3 in lymphoblastoid cell line. We further found that the 8q24 functional domains more likely interacted with genomic regions containing genes enriched in critical pathways such as Wnt signaling and promoter motifs such as E2F1 and TCF3. This result suggests that the risk locus may function as a regulatory hub by physical interactions with multiple genes important for prostate carcinogenesis. Further understanding genetic effect and biological mechanism of these chromatin interactions will shed light on the newly discovered regulatory role of the risk locus in PC etiology and progression. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. LOCUS MR: Localization of unaffected spins in MR tomography and MR spectroscopy

    International Nuclear Information System (INIS)

    Matthael, D.; Haase, A.

    1986-01-01

    Different pulse sequences have been proposed for localized in vivo MR spectroscopy. For localized MR tomography and MR spectroscopy, a method is proposed, dubbed LOCUS (LOCalization of Unaffected Spins) MR. The method uses the initial saturation of regions surrounding the region of interest (ROI) in the presence of gradients. This is followed by a conventional MR study of the unaffected ROI. In animals, human extremities, and phantoms, proton MR studies demonstrated that the method provides an optimal signal-to-noise ratio, an easily variable ROI, and ROI shim. The method can be combined with two- and three-dimensional imaging, and it allows localized measurement of MR parameters. The multinuclear capability is discussed

  9. Examining the relationship between health locus of control and God Locus of Health Control: Is God an internal or external source?

    Science.gov (United States)

    Boyd, Joni M; Wilcox, Sara

    2017-11-01

    For many people, the influence of believing in a higher power can elicit powerful effects. This study examined the relationship between God control, health locus of control, and frequency of religious attendance within 838 college students through online surveys. Regression analysis showed that chance and external locus of control and frequency of religious attendance were significant and positive predictors of God Locus of Health Control. The association of powerful others external locus of control and God Locus of Health Control differed by race (stronger in non-Whites than Whites) and somewhat by gender (stronger in women than men). For some people, the role of a supreme being, or God, should be considered when designing programs for improving health behaviors.

  10. HEALTH LOCUS OF CONTROL PERCEPTION OF ADOLESCENTS, AND ITS EFFECTS ON THEIR HEALTH BEHAVIOURS

    Directory of Open Access Journals (Sweden)

    Ruhi Selcuk TABAK

    2006-04-01

    Full Text Available Main objective of this study is to investigate the relationships between health locus of control perceptions and health behaviours of adolescents as well as the effectiveness of lectures on health locus of control to them. The subjects of our study are 192 students in 6 groups of the 9. Grade students of a high school. Three groups of 108 students were randomly selected as the experiment group who were subjected to 4 class-hours specific lectures on health locus of control. The rest 84 students constituted the control group. A 34-item questionnaire for health behaviours and the Multidimensional Health Locus of Control Scale (MHLOC, were filled by the students before and after the lectures. The lectures on health locus of control increased the perception of internal health locus of control of adolescents while decreasing chance health locus of control. The differences between experiment and control groups in this aspect were found to be statistically significant. Internal health locus of control is the main source for the increase of responsibility and management of individuals on their health. The relations that were detected between students’ health behaviours and information solicitation and their perceptions of health locus of control showed that the students with higher internal health locus of control are more eager to be responsible and active for their health, especially, for the health behaviours such as physical exercise, smoking, tooth-brushing, medical check-ups so on. [TAF Prev Med Bull 2006; 5(2.000: 118-130

  11. Defective replication initiation results in locus specific chromosome breakage and a ribosomal RNA deficiency in yeast.

    Directory of Open Access Journals (Sweden)

    Joseph C Sanchez

    2017-10-01

    Full Text Available A form of dwarfism known as Meier-Gorlin syndrome (MGS is caused by recessive mutations in one of six different genes (ORC1, ORC4, ORC6, CDC6, CDT1, and MCM5. These genes encode components of the pre-replication complex, which assembles at origins of replication prior to S phase. Also, variants in two additional replication initiation genes have joined the list of causative mutations for MGS (Geminin and CDC45. The identity of the causative MGS genetic variants strongly suggests that some aspect of replication is amiss in MGS patients; however, little evidence has been obtained regarding what aspect of chromosome replication is faulty. Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C. We find that yeast cells with the orc4Y232C allele have a prolonged S-phase, due to compromised replication initiation at the ribosomal DNA (rDNA locus located on chromosome XII. The inability to initiate replication at the rDNA locus results in chromosome breakage and a severely reduced rDNA copy number in the survivors, presumably helping to ensure complete replication of chromosome XII. Although reducing rDNA copy number may help ensure complete chromosome replication, orc4Y232C cells struggle to meet the high demand for ribosomal RNA synthesis. This finding provides additional evidence linking two essential cellular pathways-DNA replication and ribosome biogenesis.

  12. Defective replication initiation results in locus specific chromosome breakage and a ribosomal RNA deficiency in yeast.

    Science.gov (United States)

    Sanchez, Joseph C; Kwan, Elizabeth X; Pohl, Thomas J; Amemiya, Haley M; Raghuraman, M K; Brewer, Bonita J

    2017-10-01

    A form of dwarfism known as Meier-Gorlin syndrome (MGS) is caused by recessive mutations in one of six different genes (ORC1, ORC4, ORC6, CDC6, CDT1, and MCM5). These genes encode components of the pre-replication complex, which assembles at origins of replication prior to S phase. Also, variants in two additional replication initiation genes have joined the list of causative mutations for MGS (Geminin and CDC45). The identity of the causative MGS genetic variants strongly suggests that some aspect of replication is amiss in MGS patients; however, little evidence has been obtained regarding what aspect of chromosome replication is faulty. Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C). We find that yeast cells with the orc4Y232C allele have a prolonged S-phase, due to compromised replication initiation at the ribosomal DNA (rDNA) locus located on chromosome XII. The inability to initiate replication at the rDNA locus results in chromosome breakage and a severely reduced rDNA copy number in the survivors, presumably helping to ensure complete replication of chromosome XII. Although reducing rDNA copy number may help ensure complete chromosome replication, orc4Y232C cells struggle to meet the high demand for ribosomal RNA synthesis. This finding provides additional evidence linking two essential cellular pathways-DNA replication and ribosome biogenesis.

  13. Factor structure, reliability, and validity of the Levenson's Locus of Control Scale in Iranian infertile people.

    Science.gov (United States)

    Maroufizadeh, Saman; Omani Samani, Reza; Amini, Payam; Navid, Behnaz

    2016-09-01

    This study examined psychometric properties of the Levenson's Locus of Control Scale among Iranian infertile patients. In all, 312 infertile patients completed the Levenson's Locus of Control Scale and Hospital Anxiety and Depression Scale. The confirmatory factor analysis indicated that the original three-factor model of Levenson's Locus of Control Scale was adequate ( χ 2 / df = 2.139; goodness-of-fit index = 0.88; root mean square error of approximation = 0.061; and standardized root mean square residual = 0.076). The Cronbach's alpha of the subscales ranged from 0.56 to 0.67. The Levenson's Locus of Control Scale subscales significantly correlated with anxiety and depression, showing an acceptable convergent validity. In conclusion, the Levenson's Locus of Control Scale has adequate reliability and validity and can be used to measure locus of control orientation in Iranian infertile patients.

  14. Locus of the apices of projectile trajectories under constant drag

    Science.gov (United States)

    Hernández-Saldaña, H.

    2017-11-01

    Using the hodograph method, we present an analytical solution for projectile coplanar motion under constant drag, parametrised by the velocity angle. We find the locus formed by the apices of the projectile trajectories, and discuss its implementation for the motion of a particle on an inclined plane in presence of Coulomb friction. The range and time of flight are obtained numerically, and we find that the optimal launching angle is smaller than in the drag-free case. This is a good example of a problem with constant dissipation of energy that includes curvature; it is appropriate for intermediate courses of mechanics.

  15. Measurement of supernatural belief: sex differences and locus of control.

    Science.gov (United States)

    Randall, T M; Desrosiers, M

    1980-10-01

    Although we live in an age dominated by science and technology, there exists an increasingly popular anti-science sentiment. This study describes the development of a scale to assess the degree of personal acceptance of supernatural causality versus acceptance of scientific explanation. In addition to the psychometric data concerning validity and reliability of the scale, data are presented which showed the personality factor of supernaturalism to be independent of orthodox religious attitudes. Results indicated a significantly greater supernatural acceptance for women, and a positive relation of supernaturalism with external locus of control.

  16. Locus de control y conocimiento, actitud y práctica contraceptivas entre adolescentes universitarios

    OpenAIRE

    Alves, Aline Salheb; Lopes, Maria Helena Baena de Moraes

    2010-01-01

    OBJECTIVE: To assess the relationship between locus of control and knowledge, attitude and practice regarding pill and condom use among university students. METHODS: The inquiry was developed in Campinas, a city in Southeastern Brazil, in 2006. A total of 295 adolescent newcomers to a public university answered a structured questionnaire and Levenson's multidimensional locus of control scale. The scores of the dimensions of locus of control were calculated and Spearman's correlation coefficie...

  17. Locus of Control and Career Interest of Sophomore Accountancy Students: Basis for Employment Path

    OpenAIRE

    Jovielyn Mañibo; Elna Lopez

    2014-01-01

    This academic undertaking sought to determine the relationship between the locus of control and career interest of the respondents towards their future employment. The objectives of the study were to determine the respondents’ locus of control and career interest; to find if there is a significant relationship between the respondents’ locus of control and career interest and to develop an action plan that will gauge the students’ employment success as to their chosen field. In ...

  18. Characterization of additional rabbit IgM allotypes and the effect of suppression of a VH locus allotypes on the expression of n Cμ locus allotype

    International Nuclear Information System (INIS)

    Gilman-Sachs, A.; Roux, K.H.; Horing, W.J.; Dray, S.

    1982-01-01

    Anti-allotype antisera were produced that identified eight rabbit IgM allotypic specificities, n80, n81, n82, n83, n84, n85, n86, and n87. The n locus Cμ genes controlling these IgM allotypic specificities are closely linked to the a (VH subgroup) locus. The genes controlling these allotypic specificities were found to be in the heavy chain chromosomal region and were assigned to 11 haplotypes present in our rabbit colony. The n locus and a locus genes appeared in the haplotypes in six combinations: a 1 n 81 , a 2 n/sup 81,n87/, a 1 n/sup 80,83/, a 2 n/sup 80,82,87/, a 3 n/sup 81,84,85/ and a 3 n/sup 80,84,86,87/. By radioprecipitation analysis, 70 to 80% of serum IgM reacts with the antiserum directed to each n locus allotypic specificity found encoded in one haplotype; thus, each allotypic specificity of the haplotype is present on the same IgM molecule. When sera from a locus allotype-suppressed homozygous rabbits were tested for expression of each n locus allotypic specificity, n80, n81, and n87 were still expressed, whereas n82, n83, n84, n85, and n86 were not. These data provide direct evidence that some IgM specificities are expressed independently of the a locus (i.e., ''true''), and other s are dependent on the expression of an a locus specificity (i.e., conformational). The expression of the ''true'' allotypic specificities probably reflects genetic control of the germline Cμ gene, and the expression of ''conformationally dependent'' allotypic specificities probably reflects the interaction of VH and Cμ gene segments. This distinction is important and must be recognized when evaluating the genetics and structure of the IgM molecule

  19. External locus of control contributes to racial disparities in memory and reasoning training gains in ACTIVE

    Science.gov (United States)

    Zahodne, Laura B.; Meyer, Oanh L.; Choi, Eunhee; Thomas, Michael L.; Willis, Sherry L.; Marsiske, Michael; Gross, Alden L.; Rebok, George W.; Parisi, Jeanine M.

    2015-01-01

    Racial disparities in cognitive outcomes may be partly explained by differences in locus of control. African Americans report more external locus of control than non-Hispanic Whites, and external locus of control is associated with poorer health and cognition. The aims of this study were to compare cognitive training gains between African American and non-Hispanic White participants in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study and determine whether racial differences in training gains are mediated by locus of control. The sample comprised 2,062 (26% African American) adults aged 65 and older who participated in memory, reasoning, or speed training. Latent growth curve models evaluated predictors of 10-year cognitive trajectories separately by training group. Multiple group modeling examined associations between training gains and locus of control across racial groups. Compared to non-Hispanic Whites, African Americans evidenced less improvement in memory and reasoning performance after training. These effects were partially mediated by locus of control, controlling for age, sex, education, health, depression, testing site, and initial cognitive ability. African Americans reported more external locus of control, which was associated with smaller training gains. External locus of control also had a stronger negative association with reasoning training gain for African Americans than for Whites. No racial difference in training gain was identified for speed training. Future intervention research with African Americans should test whether explicitly targeting external locus of control leads to greater cognitive improvement following cognitive training. PMID:26237116

  20. External locus of control contributes to racial disparities in memory and reasoning training gains in ACTIVE.

    Science.gov (United States)

    Zahodne, Laura B; Meyer, Oanh L; Choi, Eunhee; Thomas, Michael L; Willis, Sherry L; Marsiske, Michael; Gross, Alden L; Rebok, George W; Parisi, Jeanine M

    2015-09-01

    Racial disparities in cognitive outcomes may be partly explained by differences in locus of control. African Americans report more external locus of control than non-Hispanic Whites, and external locus of control is associated with poorer health and cognition. The aims of this study were to compare cognitive training gains between African American and non-Hispanic White participants in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study and determine whether racial differences in training gains are mediated by locus of control. The sample comprised 2,062 (26% African American) adults aged 65 and older who participated in memory, reasoning, or speed training. Latent growth curve models evaluated predictors of 10-year cognitive trajectories separately by training group. Multiple group modeling examined associations between training gains and locus of control across racial groups. Compared to non-Hispanic Whites, African Americans evidenced less improvement in memory and reasoning performance after training. These effects were partially mediated by locus of control, controlling for age, sex, education, health, depression, testing site, and initial cognitive ability. African Americans reported more external locus of control, which was associated with smaller training gains. External locus of control also had a stronger negative association with reasoning training gain for African Americans than for Whites. No racial difference in training gain was identified for speed training. Future intervention research with African Americans should test whether explicitly targeting external locus of control leads to greater cognitive improvement following cognitive training. (c) 2015 APA, all rights reserved).

  1. Single locus complementary sex determination in Hymenoptera: an "unintelligent" design?

    Directory of Open Access Journals (Sweden)

    Driessen Gerard

    2006-01-01

    Full Text Available Abstract The haplodiploid sex determining mechanism in Hymenoptera (males are haploid, females are diploid has played an important role in the evolution of this insect order. In Hymenoptera sex is usually determined by a single locus, heterozygotes are female and hemizygotes are male. Under inbreeding, homozygous diploid and sterile males occur which form a genetic burden for a population. We review life history and genetical traits that may overcome the disadvantages of single locus complementary sex determination (sl-CSD. Behavioural adaptations to avoid matings between relatives include active dispersal from natal patches and mating preferences for non-relatives. In non-social species, temporal and spatial segregation of male and female offspring reduces the burden of sl-CSD. In social species, diploid males are produced at the expense of workers and female reproductives. In some social species, diploid males and diploid male producing queens are killed by workers. Diploid male production may have played a role in the evolution or maintenance of polygyny (multiple queens and polyandry (multiple mating. Some forms of thelytoky (parthenogenetic female production increase homozygosity and are therefore incompatible with sl-CSD. We discuss a number of hypothetical adaptations to sl-CSD which should be considered in future studies of this insect order.

  2. [Locus of control in girls with anorexia readiness syndrome].

    Science.gov (United States)

    Jaros, Katarzyna; Oszwa, Urszula

    2014-01-01

    The aim of the research was to indicate whether there are differences between locus of control (LOC) in girls with anorexia readiness syndrome (ARS) and without this syndrome. There was also a question about the relationship between LOC and the tendency to respond in incorrect attitudes towards food, eating and their bodies under stress. The sample consisted of girls aged 13-18 years randomly selected from five public Polish middle and high schools. Tools: 1) Eating Attitudes Questionnaire (EAQ) by B. Ziółkowska; 2) Locus of Control Questionnaire (LOCQ) by G. Krasowicz, A. Kurzyp-Wojnarska, to assess LOC of the subjects. The criterion group (N=23) was formed by girls who received high score in EAQ (signs of ARS) in the first stage of research (N=189). The control group (N = 23) were girls who received a low score in EAQ (no signs of ARS). Subjects with ARS were characterized by more external LOC than girls without any signs of this syndrome (t = -2.898; p control, LOC may play a role as a mediating variable rather than a direct determinant of this syndrome.

  3. Allelism of Genes in the Ml-a locus

    DEFF Research Database (Denmark)

    Giese, Nanna Henriette; Jensen, Hans Peter; Jørgensen, Jørgen Helms

    1980-01-01

    Seven barley lines or varieties, each with a different gene at the Ml-a locus for resistance to Erysiphe graminis were intercrossed. Progeny testing of the F2s using two different fungal isolates per cross provided evidence that there are two or more loci in the Ml-a region. Apparent recombinants...... were also screened for recombination between the Hor1 and Hor2 loci which are situated either side of the Ml-a locus. The cross between Ricardo and Iso42R (Rupee) yielded one possible recombinant, with Ml-a3 and Ml-a(Rul) in the coupling phase; other recombinants had wild-type genes in the coupling...... phase. Iso20R, derived from Hordeum spontaneum 'H204', carrying Ml-a6, had an additional gene, in close coupling with Ml-a6, tentatively named Ml-aSp2 or Reglv, causing an intermediate infection type with isolate EmA30. It is suggested that Ml-a(Ar) in Emir and Ml-a(Rul), shown to differ from other Ml...

  4. Breaking bad news: patients' preferences and health locus of control.

    Science.gov (United States)

    Martins, Raquel Gomes; Carvalho, Irene Palmares

    2013-07-01

    To identify patients' preferences for models of communicating bad news and to explore how such preferences, and the reasons for the preferences, relate with personality characteristics, specifically patients' health locus of control (HLC): internal/external and 'powerful others' (PO). Seventy-two patients from an oncology clinic watched videotaped scenarios of a breaking bad news moment, selected the model they preferred, filled an HLC scale and were interviewed about their choices. Data were analyzed with Chi-square, Kruskal-Wallis and Mann-Whitney tests. Interviews were content-analyzed. 77.8% preferred an "empathic professional", 12.5% a "distanced expert" and 9.7% an "emotionally burdened expert". Preferences varied significantly with HLC scores (patients with higher internal locus of control (ILC) and lower PO preferred the empathic model), presence of cancer, age and education. Patients explained their preferences through aspects of Caring, Professionalism, Wording, Time and Hope. ILC registered significant differences in regards to Wording and Time, whereas PO was associated with Hope and Time. HLC is an important dimension that can help doctors to better know their patients. Knowing whether patients attribute their health to their own behaviors or to chance/others can help tailor the disclosure of bad news to their specific preferences. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Focus, locus, and sensus: the three dimensions of virtual experience.

    Science.gov (United States)

    Waterworth, E L; Waterworth, J A

    2001-04-01

    A model of virtual/physical experience is presented, which provides a three dimensional conceptual space for virtual and augmented reality (VR and AR) comprising the dimensions of focus, locus, and sensus. Focus is most closely related to what is generally termed presence in the VR literature. When in a virtual environment, presence is typically shared between the VR and the physical world. "Breaks in presence" are actually shifts of presence away from the VR and toward the external environment. But we can also have "breaks in presence" when attention moves toward absence--when an observer is not attending to stimuli present in the virtual environment, nor to stimuli present in the surrounding physical environment--when the observer is present in neither the virtual nor the physical world. We thus have two dimensions of presence: focus of attention (between presence and absence) and the locus of attention (the virtual vs. the physical world). A third dimension is the sensus of attention--the level of arousal determining whether the observer is highly conscious or relatively unconscious while interacting with the environment. After expanding on each of these three dimensions of experience in relation to VR, we present a couple of educational examples as illustrations, and also relate our model to a suggested spectrum of evaluation methods for virtual environments.

  6. Digital karyotyping reveals probable target genes at 7q21.3 locus in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Wang Shengyue

    2011-07-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is a worldwide malignant liver tumor with high incidence in China. Subchromosomal amplifications and deletions accounted for major genomic alterations occurred in HCC. Digital karyotyping was an effective method for analyzing genome-wide chromosomal aberrations at high resolution. Methods A digital karyotyping library of HCC was constructed and 454 Genome Sequencer FLX System (Roche was applied in large scale sequencing of the library. Digital Karyotyping Data Viewer software was used to analyze genomic amplifications and deletions. Genomic amplifications of genes detected by digital karyotyping were examined by real-time quantitative PCR. The mRNA expression level of these genes in tumorous and paired nontumorous tissues was also detected by real-time quantitative RT-PCR. Results A total of 821,252 genomic tags were obtained from the digital karyotyping library of HCC, with 529,162 tags (64% mapped to unique loci of human genome. Multiple subchromosomal amplifications and deletions were detected through analyzing the digital karyotyping data, among which the amplification of 7q21.3 drew our special attention. Validation of genes harbored within amplicons at 7q21.3 locus revealed that genomic amplification of SGCE, PEG10, DYNC1I1 and SLC25A13 occurred in 11 (21%, 11 (21%, 11 (21% and 23 (44% of the 52 HCC samples respectively. Furthermore, the mRNA expression level of SGCE, PEG10 and DYNC1I1 were significantly up-regulated in tumorous liver tissues compared with corresponding nontumorous counterparts. Conclusions Our results indicated that subchromosomal region of 7q21.3 was amplified in HCC, and SGCE, PEG10 and DYNC1I1 were probable protooncogenes located within the 7q21.3 locus.

  7. Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.

    Directory of Open Access Journals (Sweden)

    Arne S Schaefer

    2009-02-01

    Full Text Available Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33-2.94; P = 6.9 x 10(-4 for generalized aggressive periodontitis, and 1.72 (1.06-2.76; P = 2.6 x 10(-2 for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases.

  8. Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus

    DEFF Research Database (Denmark)

    von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael

    2013-01-01

    The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from...... Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing....... Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance...

  9. CDKN2B expression and subcutaneous adipose tissue expandability: Possible influence of the 9p21 atherosclerosis locus

    Energy Technology Data Exchange (ETDEWEB)

    Svensson, Per-Arne; Wahlstrand, Björn; Olsson, Maja [Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg (Sweden); Froguel, Philippe; Falchi, Mario [Department of Genomics of Common Disease, School of Public Health, Imperial College London (United Kingdom); Bergman, Richard N. [Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA (United States); McTernan, Philip G. [Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry (United Kingdom); Hedner, Thomas; Carlsson, Lena M.S. [Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg (Sweden); Jacobson, Peter, E-mail: peter.jacobson@medfak.gu.se [Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg (Sweden)

    2014-04-18

    Highlights: • The tumor suppressor gene CDKN2B is highly expressed in human adipose tissue. • Risk alleles at the 9p21 locus modify CDKN2B expression in a BMI-dependent fashion. • There is an inverse relationship between expression of CDKN2B and adipogenic genes. • CDKN2B expression influences to postprandial triacylglycerol clearance. • CDKN2B expression in adipose tissue is linked to markers of hepatic steatosis. - Abstract: Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis.

  10. Sexual and contraceptives attitudes, the locus of health control and self-esteem among higher education students

    Directory of Open Access Journals (Sweden)

    José Manuel da Silva Vilelas Janeiro

    2014-09-01

    Full Text Available Objective: To analyze the relationship between sexual and contraceptive attitudes, the locus of health control and self-esteem among students of a private institution of higher education. Methods: Descriptive and correlational study with a quantitative approach, performed in a higher education school in Lisbon, with 152 students, from the 1st to the 4th year of undergraduate courses in Nursing, Physiotherapy, Cardiopneumology and Radiology. As research instrument, it was used a questionnaire with rating scales on ‘sexual attitudes’, ‘contraception attitudes’, ‘locus of health control’ and ‘self-esteem’. The data obtained was analyzed using descriptive and inferential statistics. Results: The majority of students (90.7% have already had sexual intercourse. Sexual attitudes were influenced by gender (p=0.0035, but not by the start of sexual activity or by the course’s year (p>0.05. Contraceptive attitudes were related to the year that students attended (p=0.031 and to gender (p=0.029. The external locus of control, on average, was higher among girls (29.2 than boys (30.1. The self-esteem increased with the student’s age (p=0.003. Conclusion: Investment in the area of sexual education is needed in the undergraduate programs, since the young people live their days in the school setting, spending little time with their families. The university should assume a special position in the development of the concept of sexuality based on the holistic perspective of the human being, promoting sexual education as essential in the construction of human identity and fundamental for health promotion doi: http://dx.doi.org/10.5020/18061230.2013.p505

  11. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

    DEFF Research Database (Denmark)

    Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L

    2017-01-01

    bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well...

  12. Are there gender differences in locus of control specific to alcohol dependence?

    Science.gov (United States)

    McPherson, Andrew; Martin, Colin R

    2017-01-01

    To investigate gender differences in locus of control in an alcohol-dependent population. Locus of control helps to explain behaviour in terms of internal (the individual is responsible) or external (outside forces, such as significant other people or chance, are responsible) elements. Past research on gender differences in locus of control in relation to alcohol dependence has shown mixed results. There is a need then to examine gender and locus of control in relation to alcohol dependence to ascertain the veracity of any locus of control differences as a function of gender. The Multidimensional Health Locus of Control form-C was administered to clients from alcohol dependence treatment centres in the West of Scotland. Independent t-tests were carried out to assess gender differences in alcohol dependence severity and internal/external aspects of locus of control. One hundred and eighty-eight (53% females) participants were recruited from a variety of alcohol dependence treatment centres. The majority of participants (72%) came from Alcoholics Anonymous groups. Women revealed a greater internal locus of control compared with men. Women also had a greater 'significant others' locus of control score than men. Men were more reliant on 'chance' and 'doctors' than women. All these trends were not, however, statistically significant. Gender differences in relation to locus of control and alcohol dependence from past studies are ambiguous. This study also found no clear statistically significant differences in locus of control orientation as a function of gender. This article helps nurses to contextualise health behaviours as a result of internal or external forces. It also helps nursing staff to better understand alcohol dependence treatment in relation to self-efficacy and control. Moreover, it highlights an important concept in health education theory. © 2016 John Wiley & Sons Ltd.

  13. Locus of control and pain: Validity of the Form C of the Multidimensional Health Locus of Control scales when used with adolescents.

    Science.gov (United States)

    Castarlenas, Elena; Solé, Ester; Racine, Mélanie; Sánchez-Rodríguez, Elisabet; Jensen, Mark P; Miró, Jordi

    2016-09-01

    The objective of this study was to examine the factor structure, reliability, and validity of the Form C of the Multidimensional Health Locus of Control scales in adolescents. A confirmatory factor analysis indicated that adequate fit of a four-factor model and the internal consistency of the scales were adequate. Criterion validity of the four scales of the Form C of the Multidimensional Health Locus of Control was also supported by significant correlations with measures of pain-related self-efficacy, anxiety, and coping strategies. The results indicate that the four Form C of the Multidimensional Health Locus of Control scale scores are reliable and valid and therefore support their use to assess pain-related locus of control beliefs in adolescents.

  14. The fester locus in Botryllus schlosseri experiences selection

    Directory of Open Access Journals (Sweden)

    Nydam Marie L

    2012-12-01

    Full Text Available Abstract Background Allorecognition, the ability of an organism to distinguish self from non-self, occurs throughout the entire tree of life. Despite the prevalence and importance of allorecognition systems, the genetic basis of allorecognition has rarely been characterized outside the well-known MHC (Major Histocompatibility Complex in vertebrates and SI (Self-Incompatibility in plants. Where loci have been identified, their evolutionary history is an open question. We have previously identified the genes involved in self/non-self recognition in the colonial ascidian Botryllus schlosseri, and we can now begin to investigate their evolution. In B. schlosseri, colonies sharing 1 or more alleles of a gene called FuHC (Fusion Histocompatibility will fuse. Protein products of a locus called fester, located ~300 kb from FuHC, have been shown to play multiple roles in the histocompatibility reaction, as activating and/or inhibitory receptors. We test whether the proteins encoded by this locus are evolving neutrally or are experiencing balancing, directional, or purifying selection. Results Nearly all of the variation in the fester locus resides within populations. The 13 housekeeping genes (12 nuclear genes and mitochondrial cytochrome oxidase I have substantially more structure among populations within groups and among groups than fester. All polymorphism statistics (Tajima's D, Fu and Li's D* and F* are significantly negative for the East Coast A-type alleles, and Fu and Li's F* statistic is significantly negative for the West Coast A-type alleles. These results are likely due to selection rather than demography, given that 10 of the housekeeping loci have no populations with significant values for any of the polymorphism statistics. The majority of codons in the fester proteins have ω values 95% posterior probability of ω values > 1. Conclusion Fester proteins are evolving non-neutrally. The polymorphism statistics are consistent with either

  15. Genetic Linkage Analysis of DFNB2 Locus with Autosomal Recessive Hearing Loss in Families Negative for GJB2 Mutations in Khuzestan Province

    Directory of Open Access Journals (Sweden)

    Parisa Tahmasebi

    2016-09-01

    Full Text Available Abstract Background: Hearing loss is a common sensory impairment in humans which half of its causes are genetic reasons. Genetic hearing loss can be divided into the two types of syndromic and non-syndromic, which 80% of non-syndromic cases is Autosomal Recessive Non-Syndromic Hearing Loss. The aim of the present research is to determine the contribution of DFNB2 locus (MYO7A gene in causing an autosomal recessive hearing loss in the one group of the deaf families of Khuzestan province. Materials and Methods: This study was conducted on 26 families with autosomal recessive hearing loss (with 4 patients and negative for GJB2 mutations in Khuzestan province. 22 families suffered from ARNSHL and 4 families suffered from Usher syndrome. Linkage analysis was performed by using STR (Short Tandem Repeat markers related to DFNB2 locus. Each family’s genotype was determined by PCR-PAGE method. Furthermore, haplotypes drawing and LOD score calculations were performed. Results: From 26 families with hearing loss participating in this research, following genetic linkage analysis and haplotypes drawing, two families (7.7% of the families showed linkage to DFNB2 locus. One family (4.5% suffered from ARNSHL and another family suffered from Usher syndrome. Conclusion: The results of the present research show that the contribution of DFNB2 locus in causing hearing loss in the population of Khuzestan province was similar to other studies conducted in Iran and this locus with other important loci should be considered to check in the hearing loss panel.

  16. Locus of Control and Self-Esteem in Indian and White Students.

    Science.gov (United States)

    Martin, James C.

    1976-01-01

    The development and relationship of two dimensions of personality, self esteem and locus of control, were examined in a study of 763 fourth, eighth, and twelfth grade Indian and white children selected from 22 Oklahoma public schools. The students were given the Coopersmith Self-Esteem Inventory and Nowicky-Strickland Locus of Control Scale during…

  17. Self Esteem, Locus of Control and Multidimensional Perfectionism as the Predictors of Subjective Well Being

    Science.gov (United States)

    Karatas, Zeynep; Tagay, Ozlem

    2012-01-01

    The purpose of this study is to determine whether there is a relationship between self-esteem, locus of control and multidimensional perfectionism, and the extent to which the variables of self-esteem, locus of control and multidimensional perfectionism contribute to the prediction of subjective well-being. The study was carried out with 318 final…

  18. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

    NARCIS (Netherlands)

    Jiao, X. (Xiang); Aravidis, C. (Christos); Marikkannu, R. (Rajeshwari); Rantala, J. (Johanna); Picelli, S. (Simone); Adamovic, T. (Tatjana); Liu, T. (Tao); Maguire, P. (Paula); B. Kremeyer (Barbara); Luo, L. (Liping); von Holst, S. (Susanna); Kontham, V. (Vinaykumar); Thutkawkorapin, J. (Jessada); Margolin, S. (Sara); Du, Q. (Quan); Lundin, J. (Johanna); Michailidou, K. (Kyriaki); Bolla, M.K. (Manjeet K.); Wang, Q. (Qin); Dennis, J. (Joe); Lush, M. (Michael); C.B. Ambrosone (Christine); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); Antonenkova, N.N. (Natalia N.); Arndt, V. (Volker); M.W. Beckmann (Matthias); C. Blomqvist (Carl); W.J. Blot (William); Boeckx, B. (Bram); S.E. Bojesen (Stig); B. Bonnani (Bernardo); J.S. Brand (Judith S.); H. Brauch (Hiltrud); H. Brenner (Hermann); A. Broeks (Annegien); T. Brüning (Thomas); B. Burwinkel (Barbara); Cai, Q. (Qiuyin); J. Chang-Claude (Jenny); NBCS Collaborators, (); Couch, F.J. (Fergus J.); A. Cox (Angela); S.S. Cross (Simon); S.L. Deming-Halverson (Sandra); P. Devilee (Peter); I. dos Santos Silva (Isabel); Dörk, T. (Thilo); M. Eriksson (Mats); P.A. Fasching (Peter); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); H. Flyger (Henrik); M. Gabrielson (Marike); M. García-Closas (Montserrat); Giles, G.G. (Graham G.); A. González-Neira (Anna); P. Guénel (Pascal); Q. Guo (Qi); Gündert, M. (Melanie); C.A. Haiman (Christopher); Hallberg, E. (Emily); U. Hamann (Ute); P. harrington (Patricia); M.J. Hooning (Maartje); J.L. Hopper (John); Huang, G. (Guanmengqian); A. Jakubowska (Anna); M. Jones (Michael); M. Kerin (Michael); V-M. Kosma (Veli-Matti); Kristensen, V.N. (Vessela N.); Lambrechts, D. (Diether); L. Le Marchand (Loic); J. Lubinski (Jan); A. Mannermaa (Arto); J.W.M. Martens (John); A. Meindl (Alfons); R.L. Milne (Roger); A.-M. Mulligan (Anna-Marie); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); J. Peto (Julian); K. Pykäs (Katri); P. Radice (Paolo); V. Rhenius (Valerie); E.J. Sawyer (Elinor); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); C.M. Seynaeve (Caroline); Shah, M. (Mitul); J. Simard (Jacques); Southey, M.C. (Melissa C.); A.J. Swerdlow (Anthony ); T. Truong (Thérèse); Wendt, C. (Camilla); R. Winqvist (Robert); W. Zheng (Wei); kConFab/AOCS Investigators, (); J. Benítez (Javier); A.M. Dunning (Alison); P.D.P. Pharoah (Paul); D.F. Easton (Douglas); K. Czene (Kamila); P. Hall (Per); A. Lindblom (Annika)

    2017-01-01

    textabstractMost non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus

  19. Hubungan antara Locus Of Control dan Efektivitas Komunikasi antar Pribadi dengan Problem Focused Coping

    Directory of Open Access Journals (Sweden)

    Eko Sujadi

    2016-03-01

    Full Text Available Problem focused coping need to be possessed by every individual. The purposes of this research were to described locus of control, the effectiveness of interpersonal communication, problem focused coping,the correlation between locus of control with problem focused coping, andthe correlationbetween the effectiveness of interpersonal communication with problem focused coping.This research was descriptive & correlation research by using quantitative approach. Data were collected through a Likert scale questionaire and locus of controlby using inventory Rotters Internal-External Locus of Control (I-E Scale, which was the validity and reliability has been tested. The data were analyzed by percentage technique and product moment correlation. The finding of research are:  1locus of control were in the middle range between internal locus of control and external locus of control with an average as big as 11.46, 2 the general level of effectiveness of interpersonal communication is in high category, 3 the general level of problem focused coping is in high category, 4 there is correlation between locus of control withproblem focused coping, and 5 there is correlation betweeneffectiveness of interpersonal communicationwithproblem focused coping.

  20. Predictors of Parental Locus of Control in Mothers of Pre- and Early Adolescents

    Science.gov (United States)

    Freed, Rachel D.; Tompson, Martha C.

    2011-01-01

    Parental locus of control refers to parents' perceived power and efficacy in child-rearing situations. This study explored parental locus of control and its correlates in 160 mothers of children ages 8 to 14 cross-sectionally and 1 year later. Maternal depression, maternal expressed emotion, and child internalizing and externalizing behavior were…

  1. Health Locus of Control and Preventive Behaviour among Students of Music

    Science.gov (United States)

    Spahn, Claudia; Burger, Thorsten; Hildebrandt, Horst; Seidenglanz, Karin

    2005-01-01

    The present study investigated health locus of control, preventive behaviour and previous playing-related health problems of music students; 326 students of music (58% female, mean age 22 years) filled in the Locus of Control Inventory for Illness and Health (Lohaus and Schmitt, 1989) and the Epidemiological Questionnaire for Musicians (Spahn,…

  2. Relationship of Personality and Locus of Control With Employment Outcomes among Participants with Spinal Cord Injury

    Science.gov (United States)

    Krause, James S.; Broderick, Lynne

    2006-01-01

    We investigated relationships among personality, locus of control, and current post-injury employment status for 1,391 participants with spinal cord injury. Participants with higher internality locus-of-control scores and activity scores (personality) reported more favorable employment outcomes. Higher scores on chance and powerful others (locus…

  3. The Relationship between the Perception of Own Locus of Control and Aggression of Adolescent Boys

    Science.gov (United States)

    Breet, Lettie; Myburgh, Chris; Poggenpoel, Marie

    2010-01-01

    Aggression is increasingly seen in most parts of South African society. Aggressive behaviour of boys in secondary school often results from frustrations caused by perceived high expectations of others regarding the role, locus of control, and personality of boys. Locus of control plays an important role in a person's perception concerning a…

  4. An Examination of Locus of Control, Epistemological Beliefs and Metacognitive Awareness in Preservice Early Childhood Teachers

    Science.gov (United States)

    Bedel, Emine Ferda

    2012-01-01

    This study aims to explore the locus of control, epistemological beliefs and metacognitive awareness levels of preservice early childhood education teachers and to determine the interrelations among these variables. 206 teacher candidates have been asked to fill out Rotter's Internal-External Locus of Control Scale, Central Epistemological Beliefs…

  5. Locus of Control as It Relates to the Teaching Style of Elementary Teachers

    Science.gov (United States)

    Ture, Abidemi

    2013-01-01

    This research explored the relationship between elementary teachers' locus of control and teaching style. This research observed elementary teachers in their classrooms coupled with data gathered from information sheets, surveys, and interviews to determine if a relationship exists between the locus of control of the elementary teachers and…

  6. Goal Orientations, Locus of Control and Academic Achievement in Prospective Teachers: An Individual Differences Perspective

    Science.gov (United States)

    Bulus, Mustafa

    2011-01-01

    The aim of this study is to investigate the role of the prospective teachers' locus of control in goal orientations and of both orientations in academic achievement. The participants were 270 undergraduate students studying in different majors at the Faculty of Education in Pamukkale University. Goal Orientations and Locus of Control Scales were…

  7. The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

    DEFF Research Database (Denmark)

    Kaur, Simranjeet; Mirza, Aashiq H.; Brorsson, Caroline Anna

    2016-01-01

    -producing INS-1E cells and the genetic and regulatory architecture of the ERBB3 locus to provide insights to how rs2292239 may confer disease susceptibility. rs2292239 strongly correlated with residual β-cell function and metabolic control in children with T1D. ERBB3 locus associated lncRNA (NONHSAG011351...

  8. Social Self-Efficacy, Academic Locus of Control, and Internet Addiction

    Science.gov (United States)

    Iskender, Murat; Akin, Ahmet

    2010-01-01

    The purpose of this research is to examine the relationship of internet addiction, social self-efficacy, and academic locus of control. Participants were 311 university students who completed a questionnaire package that included the Online Cognition Scale, the Academic Locus of Control Scale, and the Perceived Social Self-efficacy Scale. The…

  9. Authoritarian Child Rearing, Parental Locus of Control, and the Child's Behavior Style.

    Science.gov (United States)

    Janssens, Jan M. A. M.

    1994-01-01

    Examined relationships among childrearing, parental locus of control about childrearing, and child's behavior style. Found that parents who perceived their child's behavior as either externalizing or internalizing had a weak internal locus of control and were more authoritarian. Perceived externalizing child behavior was positively related to…

  10. A Study to Investigate the Relationship between Locus of Control and Academic Achievement of Students

    Science.gov (United States)

    Gujjar, Aijaz Ahmed; Aijaz, Rukhma

    2014-01-01

    Motivation is regarded as the alpha and omega of learning. It is the heart of teaching learning process. Motivation is defined as an internal state that arouses, directs, and maintains the behavior over time. Thus motivation is the pivotal component of learning and locus of control which is one of the important factors it stems from. Locus of…

  11. A Locus of Control-based HIV and AIDS Risk Reduction Training ...

    African Journals Online (AJOL)

    The aim of this study was to investigate the effi cacy of a locus of control-based training programme in reducing HIV and AIDS risk among university students. The locus of control-based variables that formed the training programme were social systems control, deferment of gratifi cation, personal values and expectancies, ...

  12. Locus of Semantic Interference in Picture Naming: Evidence from Dual-Task Performance

    Science.gov (United States)

    Piai, Vitória; Roelofs, Ardi; Schriefers, Herbert

    2014-01-01

    Disagreement exists regarding the functional locus of semantic interference of distractor words in picture naming. This effect is a cornerstone of modern psycholinguistic models of word production, which assume that it arises in lexical response-selection. However, recent evidence from studies of dual-task performance suggests a locus in…

  13. The Role of Locus of Control and Feedback on Performance of ...

    African Journals Online (AJOL)

    This study examined Students' Locus of Control and Teacher Feedback using a 2x3 factorial to measure the performance of thirty-six (36) primary school students utilizing the two locus of control types and three levels of teacher feedback: no feedback, attributional feedback, and progressive feedback. No significant ...

  14. The relationship between the perception of own locus of control and ...

    African Journals Online (AJOL)

    Aggression is increasingly seen in most parts of South African society. Aggressive behaviour of boys in secondary school often results from frustrations caused by perceived high expectations of others regarding the role, locus of control, and personality of boys. Locus of control plays an important role in a person's ...

  15. Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus

    DEFF Research Database (Denmark)

    Meyer, Kerstin B; O'Reilly, Martin; Michailidou, Kyriaki

    2013-01-01

    The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of...

  16. Locus of Control, Perceptions and Attributions of Student Teachers in Educational Situations.

    Science.gov (United States)

    Kremer, Lya; Kurtz, Chaya

    Student teachers' perceptions of locus of control was investigated. Locus of control is defined as representing the extent of dependence upon inner or outer forces, the extent one is willing to invest in shaping the environment, and the perception of reinforcement as dependent upon those efforts, or upon random events. The specific questions were:…

  17. Orexin modulates behavioral fear expression through the locus coeruleus.

    Science.gov (United States)

    Soya, Shingo; Takahashi, Tohru M; McHugh, Thomas J; Maejima, Takashi; Herlitze, Stefan; Abe, Manabu; Sakimura, Kenji; Sakurai, Takeshi

    2017-11-20

    Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NA LC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NA LC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.

  18. Interrelationships of locus of control content dimensions and hopelessness.

    Science.gov (United States)

    Ward, L C; Thomas, L L

    1985-07-01

    Items from three locus of control (LOC) tests and the Beck Hopelessness Scale were administered to 197 college students. Factor analyses produced multiple factors for each LOC test, but the Beck scale proved to be unidimensional. Factor scales were constructed for each test, and scores were factor analyzed to discover common content. Each LOC test contained a salient dimension that described belief in luck, chance, or fate, and corresponding scales were well correlated. Internal control was the second common theme, with variations according to whether control was attributed to oneself or to people in general. The third common component expressed a personal helplessness or powerlessness. Each common factor was loaded by the Hopelessness Scale, which also correlated with all but one LOC factor scale.

  19. Dynamic Quantitative Trait Locus Analysis of Plant Phenomic Data.

    Science.gov (United States)

    Li, Zitong; Sillanpää, Mikko J

    2015-12-01

    Advanced platforms have recently become available for automatic and systematic quantification of plant growth and development. These new techniques can efficiently produce multiple measurements of phenotypes over time, and introduce time as an extra dimension to quantitative trait locus (QTL) studies. Functional mapping utilizes a class of statistical models for identifying QTLs associated with the growth characteristics of interest. A major benefit of functional mapping is that it integrates information over multiple timepoints, and therefore could increase the statistical power for QTL detection. We review the current development of computationally efficient functional mapping methods which provide invaluable tools for analyzing large-scale timecourse data that are readily available in our post-genome era. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. A strabismus susceptibility locus on chromosome 7p

    Science.gov (United States)

    Parikh, Vaishali; Shugart, Yin Yao; Doheny, Kimberly F.; Zhang, Jie; Li, Lan; Williams, John; Hayden, David; Craig, Brian; Capo, Hilda; Chamblee, Denise; Chen, Cathy; Collins, Mary; Dankner, Stuart; Fiergang, Dean; Guyton, David; Hunter, David; Hutcheon, Marcia; Keys, Marshall; Morrison, Nancy; Munoz, Michelle; Parks, Marshall; Plotsky, David; Protzko, Eugene; Repka, Michael X.; Sarubbi, Maria; Schnall, Bruce; Siatkowski, R. Michael; Traboulsi, Elias; Waeltermann, Joanne; Nathans, Jeremy

    2003-01-01

    Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes. PMID:14519848

  1. Hearing the zero locus of a magnetic field

    International Nuclear Information System (INIS)

    Montgomery, R.

    1995-01-01

    We investigate the ground state of a two-dimensional quantum particle in a magnetic field where the field vanishes nondegenerately along a closed curve. We show that the ground state concentrates on this curve as e/h tends to infinity, where e is the charge, and that the ground state energy grows like (e/h) 2/3 . These statements are true for any energy level, the level being fixed as the charge tends to infinity. If the magnitude of the gradient of the magnetic field is a constant b 0 along its zero locus, then we get the precise asymptotics (e/h) 2/3 (b 0 ) 2/3 E * + O(1) for every energy level. The constant E * ≅ .5698 is the infimum of the ground state energies E(β) of the anharmonic oscillator family -d 2 /dy 2 + (1/2 y 2 - β) 2 . (orig.)

  2. A novel stroke locus identified in a northern Sweden pedigree

    DEFF Research Database (Denmark)

    Janunger, T.; Nilsson-Ardnor, S.; Wiklund, P.-G.

    2009-01-01

    OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan...... to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score...... of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke...

  3. Examining the locus of age effects on complex span tasks.

    Science.gov (United States)

    McCabe, Jennifer; Hartman, Marilyn

    2003-09-01

    To investigate the locus of age effects on complex span tasks, the authors evaluated the contributions of working memory functions and processing speed. Age differences were found in measures of storage capacity, language processing speed, and lower level speed. Statistically controlling for each of these in hierarchical regressions substantially reduced, but did not eliminate, the complex span age effect. Accounting for lower level speed and storage, however, removed essentially the entire age effect, suggesting that both functions play important and independent roles. Additional evidence for the role of storage capacity was the absence of complex span age differences with span size calibrated to individual word span performance. Explanations for age differences based on inhibition and concurrent task performamce were not supported.

  4. Association between the ABO locus and hematological traits in Korean

    Directory of Open Access Journals (Sweden)

    Hong Kyung-Won

    2012-09-01

    Full Text Available Abstract Background Recently, genome-wide association studies identified a pleiotropic gene locus, ABO, as being significantly associated with hematological traits. To confirm the effects of ABO on hematological traits, we examined the link between the ABO locus and hematological traits in Korean population-based cohorts. Results Six tagging SNPs for ABO were analyzed with regard to their effects on hematological traits [white blood cell count (WBC, red blood cell count (RBC, platelet (Plat, mean corpuscular volume (MCV, and mean corpuscular haemoglobin concentration (MCHC]. Linear regression analyses were performed, controlling for recruitment center, sex, and age as covariates. Of the 6 tagging SNPs, 3 (rs2073823, rs8176720, and rs495828 and 3 (rs2073823, rs8176717, and rs687289 were significantly associated with RBC and MCV, respectively (Bonferroni correction p-value criteria r2s = 0.99. Of the remaining 3 SNPs (rs8176720, rs8176717 and rs687289, rs8176717 generated an independent signal with moderate p-value (= 0.045 when it was adjusted for by rs2073823 (the most significant SNP. We also identified a copy number variation (CNV that was tagged by the SNP rs8176717, the minor allele of which correlated with the deletion allele of CNV. Our haplotype analysis indicated that the haplotype that contained the CNV deletion was significantly associated with MCV (β ± se = 0.363 ± 0.118, p =2.09 × 10-3. Conclusions Our findings confirm that ABO is one of the genetic factors that are associated with hematological traits in the Korean population. This result is notable, because GWASs fail to evaluate the link between a CNV and phenotype traits.

  5. The locus of semantic interference in picture naming

    Directory of Open Access Journals (Sweden)

    Pedro Macizo

    2003-01-01

    Full Text Available El locus del efecto de interferencia semántica en la denominación de dibujos. En los experimentos que se presentan se utilizó el procedimiento de priming enmascarado para explorar el locus del efecto de interferencia semántica. Para ello se manipuló la naturaleza de la tarea (denominación y decisión de género, el tipo de relación entre el prime y el target (semántica y fonológica y el tiempo de presentación del prime. Los resultados indicaron que el efecto de interferencia semántica aparece en las tareas de denominación (Experimento 1 y de decisión de género (Experimento 2, con tiempos de presentación del prime de 100 ms. Este resultado replica el efecto encontrado por otros investigadores y lo extiende a la tarea de decisión de género. Por otro lado, el efecto de facilitación fonológica no apareció en la tarea de decisión de género (Experimento 3. Este patrón de resultados sugiere que el efecto de interferencia semántica es consecuencia de procesos que ocurren en el nivel de representación del lemma, y que la tarea de decisión de género no está influenciada por la activación fonológica.

  6. The Contribution of Locus of Control to Academic Procrastination in Islamic Education Management Students in Indonesia

    Directory of Open Access Journals (Sweden)

    Juliana Batubara

    2017-02-01

    Full Text Available This study aimed to describe the locus of control and academic procrastination, and investigate whether there is significance contributions of locus of control on student academic procrastination. This research was conducted by the Ex post-facto method was used in this study, where the data taken from two set of questionnaires. Proportional Stratified Random Sampling was used. There were 107 students involved this study. The results showed that the locus of control is in average level, meanwhile, and the students’ academic achievement was high. The study also showed that there is a significant contribution between the locus of control on students' academic procrastination. The article concludes that the importance that locus control for procrastination research, and with suggestions for educators who work with students who are adversely affected by procrastination.

  7. Life events, locus of control, and behavioral problems among Chinese adolescents.

    Science.gov (United States)

    Liu, X; Kurita, H; Uchiyama, M; Okawa, M; Liu, L; Ma, D

    2000-12-01

    This study examined associations of life events and locus of control with behavioral problems among 1,365 Chinese adolescents by using the Youth Self-Report (YSR), Adolescent Self-Rating Life Events Checklist (ASLEC), and the Nowicki-Strickland Locus of Control Scale for Children. Results indicated that the overall prevalence of behavioral and emotional problems was 10.7% (95% CI = 9.9-11.5%). Logistic-regression analyses showed that a total of 13 negative life events mainly coming from academic domain and interpersonal relationships, high life-stress score, and high external locus score significantly increased the risk for behavioral problems. Life stress and locus of control significantly interacted with behavioral problems. These findings support the linkage between stressful life events and psychopathology in a general population of adolescents from mainland China, and demonstrate the stress-moderating effects of locus of control on psychopathology as well.

  8. How Multidimensional Health Locus of Control predicts utilization of emergency and inpatient hospital services.

    Science.gov (United States)

    Mautner, Dawn; Peterson, Bridget; Cunningham, Amy; Ku, Bon; Scott, Kevin; LaNoue, Marianna

    2017-03-01

    Health locus of control may be an important predictor of health care utilization. We analyzed associations between health locus of control and frequency of emergency department visits and hospital admissions, and investigated self-rated health as a potential mediator. Overall, 863 patients in an urban emergency department completed the Multidimensional Health Locus of Control instrument, and self-reported emergency department use and hospital admissions in the last year. We found small but significant associations between Multidimensional Health Locus of Control and utilization, all of which were mediated by self-rated health. We conclude that interventions to shift health locus of control may change patients' perceptions of their own health, thereby impacting utilization.

  9. Hitch-hiking from HRAS1 to the WAGR locus with CMGT markers

    Energy Technology Data Exchange (ETDEWEB)

    Bickmore, W.; Christie, S.; van Heyningen, V.; Hastie, N.D.; Porteous, D.J.

    1988-01-11

    The clinical association of Wilms' tumor with aniridia, genitourinary abnormalities and mental retardation (WAGR syndrome) is characterized cytogenetically by variable length, constitutional deletion of the short arm of chromosome 11, which always includes at least part of band 11p13. HRAS1-selected chromosome mediated gene transfer (CMGT) generated a transformant, E65-6, in which the only human genes retained map either to band 11p13 or, with HRAS1, in the region 11p15.4-pter. Human recombinants isolated from E65-6 were mapped to a panel of five WAGR deletion hybrids and two clinically related translocations. The authors show that E65-6 is enriched -400-fold for 11p15.4-pter markers and -200-fold for 11p13 markers. Hitch-hiking from HRAS1 with CMGT markers has allowed us to define seven discrete intervals which subtend band 11p13. Both associated translocations co-locate within the smallest region of overlap with the WAGR locus, which has been redefined by identifying a new interval closer than FSHB.

  10. Identification of Coxiella burnetii genotypes in Croatia using multi-locus VNTR analysis.

    Science.gov (United States)

    Račić, Ivana; Spičić, Silvio; Galov, Ana; Duvnjak, Sanja; Zdelar-Tuk, Maja; Vujnović, Anja; Habrun, Boris; Cvetnić, Zeljko

    2014-10-10

    Although Q fever affects humans and animals in Croatia, we are unaware of genotyping studies of Croatian strains of the causative pathogen Coxiella burnetii, which would greatly assist monitoring and control efforts. Here 3261 human and animal samples were screened for C. burnetii DNA by conventional PCR, and 335 (10.3%) were positive. Of these positive samples, 82 were genotyped at 17 loci using the relatively new method of multi-locus variable number tandem repeat analysis (MLVA). We identified 13 C. burnetii genotypes not previously reported anywhere in the world. Two of these 13 genotypes are typical of the continental part of Croatia and share more similarity with genotypes outside Croatia than with genotypes within the country. The remaining 11 novel genotypes are typical of the coastal part of Croatia and show more similarity to one another than to genotypes outside the country. Our findings shed new light on the phylogeny of C. burnetii strains and may help establish MLVA as a standard technique for Coxiella genotyping. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. MULTIPLE-LOCUS VARIABLE-NUMBER TANDEM REPEAT ANALYSIS OF BRUCELLA ISOLATES FROM THAILAND.

    Science.gov (United States)

    Kumkrong, Khurawan; Chankate, Phanita; Tonyoung, Wittawat; Intarapuk, Apiradee; Kerdsin, Anusak; Kalambaheti, Thareerat

    2017-01-01

    Brucellosis-induced abortion can result in significant economic loss to farm animals. Brucellosis can be transmitted to humans during slaughter of infected animals or via consumption of contaminated food products. Strain identification of Brucella isolates can reveal the route of transmission. Brucella strains were isolated from vaginal swabs of farm animal, cow milk and from human blood cultures. Multiplex PCR was used to identify Brucella species, and owing to high DNA homology among Brucella isolates, multiple-locus variable-number tandem repeat analysis (MLVA) based on the number of tandem repeats at 16 different genomic loci was used for strain identification. Multiplex PCR categorized the isolates into B. abortus (n = 7), B. melitensis (n = 37), B. suis (n = 3), and 5 of unknown Brucella spp. MLVA-16 clustering analysis differentiated the strains into various genotypes, with Brucella isolates from the same geographic region being closely related, and revealed that the Thai isolates were phylogenetically distinct from those in other countries, including within the Southeast Asian region. Thus, MLVA-16 typing has utility in epidemiological studies.

  12. Identification of a Major Locus Contributing to Erythrocyte 2,3-Diphosphoglycerate Variability in Hooded (Long-Evans) Rats

    Science.gov (United States)

    Noble, N. A.; Brewer, G. J.

    1977-01-01

    The erythrocyte glycolytic intermediate 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) play an important role in oxygen transport and delivery by binding to hemoglobin (Hb) and reducing its affinity for oxygen. Considerable quantitative variability in the levels of DPG and ATP exists in human populations and in a population of hooded (Long-Evans) rats we have studied. This paper presents the results of studies on the genetic component of DPG-level variation in an outbred population of hooded rats. Beginning with about 100 rats, a two-way selection experiment was initiated. Pairs of rats with the highest DPG levels were mated to produce a High-DPG rat strain and animals with the lowest DPG levels were mated to produce a Low-DPG strain. Mean DPG levels responded rapidly to selection and, from generation 3 on, the differences between strain means were highly significant. Ten High-DPG strain rats were intercrossed with 10 Low-DPG strain rats of generation 10 to produce an F1 generation in which the DPG levels were almost as high as those of High-DPG animals. This indicates partial dominance of High-DPG alleles. The F2 DPG-level distribution showed two distinct subpopulations. The high DPG subpopulation contained three times as many animals as the low DPG subpopulation. From these results and the statistical analyses performed, it was concluded that the DPG differences between strains were due to an allelic difference at one major locus, the allele carried by the High-DPG strain showing partial dominance over the allele carried by the Low-DPG strain. It appears that this locus may also effect ATP levels to a large extent and is polymorphic in hooded rat populations. Identification of this locus gives us a useful tool for studies of the physiological effects of DPG variability, as well as providing an example of a major gene effect in a quantitatively varying trait. PMID:863239

  13. Multi-locus sequence typing of Bartonella henselae isolates from three continents reveals hypervirulent and feline-associated clones.

    Directory of Open Access Journals (Sweden)

    Mardjan Arvand

    Full Text Available Bartonella henselae is a zoonotic pathogen and the causative agent of cat scratch disease and a variety of other disease manifestations in humans. Previous investigations have suggested that a limited subset of B. henselae isolates may be associated with human disease. In the present study, 182 human and feline B. henselae isolates from Europe, North America and Australia were analysed by multi-locus sequence typing (MLST to detect any associations between sequence type (ST, host species and geographical distribution of the isolates. A total of 14 sequence types were detected, but over 66% (16/24 of the isolates recovered from human disease corresponded to a single genotype, ST1, and this type was detected in all three continents. In contrast, 27.2% (43/158 of the feline isolates corresponded to ST7, but this ST was not recovered from humans and was restricted to Europe. The difference in host association of STs 1 (human and 7 (feline was statistically significant (P< or =0.001. eBURST analysis assigned the 14 STs to three clonal lineages, which contained two or more STs, and a singleton comprising ST7. These groups were broadly consistent with a neighbour-joining tree, although splits decomposition analysis was indicative of a history of recombination. These data indicate that B. henselae lineages differ in their virulence properties for humans and contribute to a better understanding of the population structure of B. henselae.

  14. Targeting the human lysozyme gene on bovine αs1- casein gene ...

    African Journals Online (AJOL)

    Targeting an exogenous gene into a favorable gene locus and for expression under endogenous regulators is an ideal method in mammary gland bioreactor research. For this purpose, a gene targeting vector was constructed to targeting the human lysozyme gene on bovine αs1-casein gene locus. In this case, the ...

  15. Association of a Network of Interferon-Stimulated Genes with a Locus Encoding a Negative Regulator of Non-conventional IKK Kinases and IFNB1

    Directory of Open Access Journals (Sweden)

    Saloua Jeidane

    2016-10-01

    Full Text Available Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL linked in trans to the expression of 190 gene transcripts and in cis to the expression of only two genes, one of which was Ypel5. Most of the trans-expression QTL genes were interferon-stimulated genes (ISGs, and their expression in mouse macrophage cell lines was stimulated in an IFNB1-dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE. We thus found that the Ypel5 gene (contained in a locus linked to a network of ISGs in mice is a negative regulator of IFNB1 production and innate immune responses that interacts functionally and physically with TBK1/IKBKE kinases.

  16. Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of macrophage growth locus A (MglA) protein from Francisella tularensis

    International Nuclear Information System (INIS)

    Subburaman, Priadarsini; Austin, Brian P.; Shaw, Gary X.; Waugh, David S.; Ji, Xinhua

    2010-01-01

    The macrophage growth locus A (MglA) protein from F. tularensis crystallized in the hexagonal space group P6 1 or P6 5 , with unit-cell parameters a = b = 125, c = 54 Å. Francisella tularensis, a potential bioweapon, causes a rare infectious disease called tularemia in humans and animals. The macrophage growth locus A (MglA) protein from F. tularensis associates with RNA polymerase to positively regulate the expression of multiple virulence factors that are required for its survival and replication within macrophages. The MglA protein was overproduced in Escherichia coli, purified and crystallized. The crystals diffracted to 7.5 Å resolution at the Advanced Photon Source, Argonne National Laboratory and belonged to the hexagonal space group P6 1 or P6 5 , with unit-cell parameters a = b = 125, c = 54 Å

  17. The relationship between the INTERMED patient complexity instrument and Level of Care Utilisation System (LOCUS).

    Science.gov (United States)

    Thurber, Steven; Wilson, Ann; Realmuto, George; Specker, Sheila

    2018-03-01

    To investigate the concurrent and criterion validity of two independently developed measurement instruments, INTERMED and LOCUS, designed to improve the treatment and clinical management of patients with complex symptom manifestations. Participants (N = 66) were selected from hospital records based on the complexity of presenting symptoms, with tripartite diagnoses across biological, psychiatric and addiction domains. Biopsychosocial information from hospital records were submitted to INTERMED and LOCUS grids. In addition, Global Assessment of Functioning (GAF) ratings were gathered for statistical analyses. The product moment correlation between INTERMED and LOCUS was 0.609 (p = .01). Inverse zero-order correlations for INTERMED and LOCUS total score and GAF were obtained. However, only the beta weight for LOCUS and GAF was significant. An exploratory principal components analysis further illuminated areas of convergence between the instruments. INTERMED and LOCUS demonstrated shared variance. INTERMED appeared more sensitive to complex medical conditions and severe physiological reactions, whereas LOCUS findings are more strongly related to psychiatric symptoms. Implications are discussed.

  18. Work stress and emotional exhaustion in nurses: the mediating role of internal locus of control.

    Science.gov (United States)

    Partlak Günüşen, Neslihan; Ustün, Besti; Erdem, Sabri

    2014-01-01

    Burnout is a major problem for nursing. There is a strong relationship between work stress and emotional exhaustion. Although studies report a negative correlation between the internal locus of control and emotional exhaustion and work stress, the number of studies available on the subject is limited. This study intends to examine the extent to which the relationship between work stress and emotional exhaustion is mediated by nurses' internal locus of control. The study adopted a cross-sectional survey design. The data were analyzed using structural equation modeling techniques. The study sample consisted of 347 nurses who worked in a university hospital in Izmir, Turkey and who agreed to participate in the study. The Work-Related Strain Inventory was used to evaluate the nurses' work stress level, Maslach Burnout Inventory was used to evaluate their emotional exhaustion levels, and the Locus of Control Scale was used to evaluate the internal locus of control. The variables of the study were based on the Neuman Systems Model. Work stress was positively related to internal locus of control (β3 = .21, p 0.1). Internal locus of control was negatively related to emotional exhaustion (β = -.14, p Work stress is directly (β = .87, p Work stress is directly (β = .87, p work stress was mediated, the impact of internal locus of control was limited. It is recommended that different variables be included in future studies so that they can mediate the relationship between work stress and emotional exhaustion.

  19. The Relationship between Health Locus of Control and Health Behaviors in Emergency Medicine Personnel.

    Science.gov (United States)

    Pourhoseinzadeh, Mansour; Gheibizadeh, Mahin; Moradikalboland, Mehrnaz

    2017-10-01

    Health locus of control defined as individual beliefs based on past experiences in health issues and having external or internal control over them, could affect health. Health locus of control plays a role in health behaviors. We aimed to investigate the relationship between health locus of control and health behavior in emergency medical personnel in Ahvaz during 2016. This is a cross-sectional descriptive study, which began in August 2016 for a period of six months on 215 emergency medical personnel in Ahvaz who were selected randomly. The data were collected by a demographic questionnaire, Rotter's locus of control questionnaire, and health behavior questionnaire and analyzed using SPSS software, version 22. The correlation between variables was estimated by Pearson's correlation coefficient and independent t test. The level of significance for all statistical tests was set at 0.05. We found no significant relationship between health locus of control (external and internal) and health behavior (P>0.05).Health behaviors were very good in terms of personal health (86.5%), nutrition (53%), and sleep and rest (48.4%), and poor in terms of physical activity (52.6%) and stress management (79.5%). Furthermore, 79.5% of the emergency personnel, in general, had poor heath behaviors. Leaders and officials in the field of health must necessarily design programs in relation to health locus of control and the factors developing and affecting it as well as the role of health locus of control in doing correct behaviors.

  20. Weight loss maintenance in relation to locus of control: The MedWeight study.

    Science.gov (United States)

    Anastasiou, Costas A; Fappa, Evaggelia; Karfopoulou, Eleni; Gkza, Anastasia; Yannakoulia, Mary

    2015-08-01

    Locus of control, i.e. the degree of an individual's belief on the control of his/her life, has been related to many health outcomes, including weight loss in overweight/obese individuals. No information is available on the impact of locus of control in maintaining weight loss. We aimed to investigate the effect of locus of control in weight loss maintenance and explore potential associations with lifestyle factors. Study participants included 239 individuals (41% males) who had lost at least 10% of body weight in the past and either maintained the loss (maintainers: weight maintenance of at least 10% of initial weight) or regained it (regainers). Locus of control was defined by a relevant multi-dimensional scale; participants were categorised to internals and externals, based on "internal" and "others" sub-scales. A significant interaction was found between locus of control and weight loss maintenance status (p locus of control. Individualised treatment, according to locus of control, may increase weight loss maintenance rates in former overweight/obese individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Internal health locus of control predicts willingness to track health behaviors online and with smartphone applications.

    Science.gov (United States)

    Bennett, Brooke L; Goldstein, Carly M; Gathright, Emily C; Hughes, Joel W; Latner, Janet D

    2017-12-01

    Given rising technology use across all demographic groups, digital interventions offer a potential strategy for increasing access to health information and care. Research is lacking on identifying individual differences that impact willingness to use digital interventions, which may affect patient engagement. Health locus of control, the amount of control an individual believes they have over their own health, may predict willingness to use mobile health (mHealth) applications ('apps') and online trackers. A cross-sectional study (n = 276) was conducted to assess college students' health locus of control beliefs and willingness to use health apps and online trackers. Internal and powerful other health locus of control beliefs predicted willingness to use health apps and online trackers while chance health locus of control beliefs did not. Individuals with internal and powerful other health locus of control beliefs are more willing than those with chance health locus of control beliefs to utilize a form of technology to monitor or change health behaviors. Health locus of control is an easy-to-assess patient characteristic providers can measure to identify which patients are more likely to utilize mHealth apps and online trackers.

  2. Relationship of emotional intelligence and health locus of control among female breast cancer patients in pakistan

    International Nuclear Information System (INIS)

    Naz, R.; Kamal, A.

    2016-01-01

    Objective: To investigate relationship between emotional intelligence and health locus of control in married women with breast cancer disease. Study Design: Cross sectional study. Place and Duration of Study: The data was collected from Nuclear Oncology and Radiology Institute (NORI Hospital) Islamabad (n=210) and from Combined Military Hospital (CMH) Rawalpindi (n=101). Data collection was completed between the period from Oct 2013 to Feb 2014. Patients and Methods: The sample was selected using non- probability sampling technique. Collected breast cancer patients sample was n= 311 whose age range was from 18-80 years. A biographical sheet that contain personal and disease information of patient, and two scales were used: Self Report Measure of Emotional Intelligence (Khan and Kamal, 2010), and Multidimensional Health Locus of Control (Wallston, Stein, and Smith, 1994) were used to assess the constructs explored in this study. Results: Results depict that there was significant positive correlation between emotional intelligence (EI), including its sub scales Emotional Self-Regulation Skills (ESRS), Emotional Self Awareness Skills (ESAS), and Interpersonal Skills Scale (ISS) with the Internal Health Locus of Control (IHLOC). Doctors Health Locus of Control (DHLOC) also have significant relationship to emotional intelligence's all sub divisions, whereas external health locus of control including Chance Health Locus of Control (CHLOC) and Powerful Other people Health Locus of Control (PHLOC) both are related to psychological distresses but it was observed in breast cancer population that chance was significantly correlated to ESAS, and ISS and powerful other people locus. Further on group comparison One Way Analysis of Variance (ANOVA) depicted no significant difference on disease stage groups. Conclusion: The strength factors of EI and HLOC are highlighted in current study. It was concluded that Emotional Intelligence (EI) and health locus of control (IHLOC, and

  3. Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy.

    Science.gov (United States)

    Marenholz, Ingo; Grosche, Sarah; Kalb, Birgit; Rüschendorf, Franz; Blümchen, Katharina; Schlags, Rupert; Harandi, Neda; Price, Mareike; Hansen, Gesine; Seidenberg, Jürgen; Röblitz, Holger; Yürek, Songül; Tschirner, Sebastian; Hong, Xiumei; Wang, Xiaobin; Homuth, Georg; Schmidt, Carsten O; Nöthen, Markus M; Hübner, Norbert; Niggemann, Bodo; Beyer, Kirsten; Lee, Young-Ae

    2017-10-20

    Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.

  4. Characterization of arrangement and expression of the beta-2 microglobulin locus in the sandbar and nurse shark.

    Science.gov (United States)

    Chen, Hao; Kshirsagar, Sarika; Jensen, Ingvill; Lau, Kevin; Simonson, Caitlin; Schluter, Samuel F

    2010-02-01

    Beta 2 microglobulin (beta2m) is an essential subunit of major histocompatibility complex (MHC) type I molecules. In this report, beta2m cDNAs were identified and sequenced from sandbar shark spleen cDNA library. Sandbar shark beta2m gene encodes one amino acid less than most teleost beta2m genes, and 3 amino acids less than mammal beta2m genes. Although sandbar shark beta2m protein contains one beta sheet less than that of human in the predicted protein structure, the overall structure of beta2m proteins is conserved during evolution. Germline gene for the beta2m in sandbar and nurse shark is present as a single locus. It contains three exons and two introns. CpG sites are evenly distributed in the shark beta2m loci. Several DNA repeat elements were also identified in the shark beta2m loci. Sequence analysis suggests that the beta2m locus is not linked to the MHC I loci in the shark genome.

  5. Genetic Linkage Analysis of the DFNB21 Locus in Autosomal Recessive Hearing Loss in Large Families from Khuzestan Province

    Directory of Open Access Journals (Sweden)

    Mahtab Khosrofar

    2017-06-01

    Full Text Available Abstract Background: Hearing loss (HL is the most common congenital defect in humans. One or two in thousand newborn babies have prelingual hearing loss. Autosomal recessive non-syndromic hearing loss (ARNSHL is the most common form of hereditary deafness. Hearing loss is more common in the developing countries which is due to genetic and environmental (cultural -health factors reasons. HL has a wide range of clinical demonstrations including: congenital or late onset, conductive or sensory-neural, syndromic or non-syndromic hearing loss. The goal of this project is to determine the portion of the DFNB21 (TECTA in ARNSHL in families with negative GJB2 gene in Khuzestan province. Materials and Methods: We studied 21 families with ARNSHL with at least 4 patients and negative for GJB2 mutations from Khuzestan province. Genetic linkage analysis was performed using STR markers linked to DFNB21 locus. Results: Following genetic linkage analysis and haplotyping, out of 21 families with ARNSHL, one family showed linkage to the DFNB21 (TECTA locus. Conclusion: The results of this project confirm other studies in Iran and give insight into the most common loci causing ARNSHL in Iran which could be helpful in research and clinic.

  6. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

    Science.gov (United States)

    Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Le Marchand, Loïc; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

    2012-01-01

    Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. PMID:22037553

  7. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

    Science.gov (United States)

    Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Marchand, Loïc Le; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

    2011-10-30

    Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

  8. [Illness concepts of children. Validation of a modified locus of control test in illness and health].

    Science.gov (United States)

    Schmidt, A; Altmann-Herz, U

    1992-12-01

    We investigated the health and illness concepts of 53 healthy children aged 8 to 14 years using a modified illness and health locus of control scale (KKG, Lohaus and Schmitt, 1989) with the scales internal, external-p (powerful others) and external-c (chance). A comparison of the results with those on self-esteem (FSK 4-6), anxiety (CMAS-R) and hopelessness (HSC) scales showed a decrease in externality, but not an increase in internality, with increasing age and a correlation between self-confidence and a more internal locus of control. The influence of children's health locus of control on treatment compliance is discussed.

  9. [Analysis of allele dropout at TH01 locus in paternity testing].

    Science.gov (United States)

    Lai, Li; Shen, Xiao-li; Xue, Shi-jie; Hu, Jie

    2013-10-01

    To analyze allele dropout at TH01 locus in paternity testing in order to determine the accurate genotype. To use a two STR loci genotyping system to verify an abnormal genotype for the TH01 locus with PCR using specific primers, cloning and DNA sequencing. A rare allele at TH01 locus named 5.2, which was undetectable with PowerPlex 21 system, was detected with an Identifiler system. Genetic variations may result in rare alleles and loci loss. To avoid misjudgment, laboratories should have a variety of methods for detecting loci loss.

  10. HPRT gene locus mutation in peripheral blood lymphocytes induced by internal exposure to radionuclides

    Energy Technology Data Exchange (ETDEWEB)

    Jingyong, Zhao; Yongzhong, Xu; Tao, Zhao; Fengmei, Cui; Liuyi, Wang; Qinhua, Lao [Suzhou Univ., Suzhou (China). Radiation Medicine Department

    2001-07-01

    HPRT gene locus mutation in peripheral blood lymphocytes induced by internal exposure to radionuclides was performed and the relationships between mutation frequency and dose were studied. Rats were injected intravenously with radionuclides, the blood was sampled at different time after injection; HPRT gene locus mutation frequency (GMF) were examined by methods of multi-nucleus cell and Brdurd assay, working out the Dose-response function. GMF rose with the increase of dose and dose-rates and were clearly interrelated. The HPRT gene locus mutation is very sensitive to radiation and may be used as a biological dosimeter.

  11. Personal networks and locus of control in large urban centers of Argentina

    Directory of Open Access Journals (Sweden)

    Pablo De Grande

    2013-12-01

    Full Text Available This study analyzes the relationship between locus of control and interpersonal relations structures in Argentina. After a representative sample (n = 1500 of households in seven major urban centers (>200,000 inhabitants, it examines the relationship between the externality of locus of control and different aspects of personal networks of each respondent. The results show that people having more relations experiment lower levels of externality of locus of control. Likewise, lower levels of externality are informed when personal ties outside the neighborhood are available, as well as ties high educational level. In this regard, significant associations are verified between control and personal relations structures.

  12. Multi locus sequence typing of Chlamydia reveals an association between Chlamydia psittaci genotypes and host species.

    Science.gov (United States)

    Pannekoek, Yvonne; Dickx, Veerle; Beeckman, Delphine S A; Jolley, Keith A; Keijzers, Wendy C; Vretou, Evangelia; Maiden, Martin C J; Vanrompay, Daisy; van der Ende, Arie

    2010-12-02

    Chlamydia comprises a group of obligate intracellular bacterial parasites responsible for a variety of diseases in humans and animals, including several zoonoses. Chlamydia trachomatis causes diseases such as trachoma, urogenital infection and lymphogranuloma venereum with severe morbidity. Chlamydia pneumoniae is a common cause of community-acquired respiratory tract infections. Chlamydia psittaci, causing zoonotic pneumonia in humans, is usually hosted by birds, while Chlamydia abortus, causing abortion and fetal death in mammals, including humans, is mainly hosted by goats and sheep. We used multi-locus sequence typing to asses the population structure of Chlamydia. In total, 132 Chlamydia isolates were analyzed, including 60 C. trachomatis, 18 C. pneumoniae, 16 C. abortus, 34 C. psittaci and one of each of C. pecorum, C. caviae, C. muridarum and C. felis. Cluster analyses utilizing the Neighbour-Joining algorithm with the maximum composite likelihood model of concatenated sequences of 7 housekeeping fragments showed that C. psittaci 84/2334 isolated from a parrot grouped together with the C. abortus isolates from goats and sheep. Cluster analyses of the individual alleles showed that in all instances C. psittaci 84/2334 formed one group with C. abortus. Moving 84/2334 from the C. psittaci group to the C. abortus group resulted in a significant increase in the number of fixed differences and elimination of the number of shared mutations between C. psittaci and C. abortus. C. psittaci M56 from a muskrat branched separately from the main group of C. psittaci isolates. C. psittaci genotypes appeared to be associated with host species. The phylogenetic tree of C. psittaci did not follow that of its host bird species, suggesting host species jumps. In conclusion, we report for the first time an association between C. psittaci genotypes with host species.

  13. Multi locus sequence typing of Chlamydia reveals an association between Chlamydia psittaci genotypes and host species.

    Directory of Open Access Journals (Sweden)

    Yvonne Pannekoek

    2010-12-01

    Full Text Available Chlamydia comprises a group of obligate intracellular bacterial parasites responsible for a variety of diseases in humans and animals, including several zoonoses. Chlamydia trachomatis causes diseases such as trachoma, urogenital infection and lymphogranuloma venereum with severe morbidity. Chlamydia pneumoniae is a common cause of community-acquired respiratory tract infections. Chlamydia psittaci, causing zoonotic pneumonia in humans, is usually hosted by birds, while Chlamydia abortus, causing abortion and fetal death in mammals, including humans, is mainly hosted by goats and sheep. We used multi-locus sequence typing to asses the population structure of Chlamydia. In total, 132 Chlamydia isolates were analyzed, including 60 C. trachomatis, 18 C. pneumoniae, 16 C. abortus, 34 C. psittaci and one of each of C. pecorum, C. caviae, C. muridarum and C. felis. Cluster analyses utilizing the Neighbour-Joining algorithm with the maximum composite likelihood model of concatenated sequences of 7 housekeeping fragments showed that C. psittaci 84/2334 isolated from a parrot grouped together with the C. abortus isolates from goats and sheep. Cluster analyses of the individual alleles showed that in all instances C. psittaci 84/2334 formed one group with C. abortus. Moving 84/2334 from the C. psittaci group to the C. abortus group resulted in a significant increase in the number of fixed differences and elimination of the number of shared mutations between C. psittaci and C. abortus. C. psittaci M56 from a muskrat branched separately from the main group of C. psittaci isolates. C. psittaci genotypes appeared to be associated with host species. The phylogenetic tree of C. psittaci did not follow that of its host bird species, suggesting host species jumps. In conclusion, we report for the first time an association between C. psittaci genotypes with host species.

  14. Contrasting mode of evolution at a coat color locus in wild and domestic pigs.

    Directory of Open Access Journals (Sweden)

    Meiying Fang

    2009-01-01

    Full Text Available Despite having only begun approximately 10,000 years ago, the process of domestication has resulted in a degree of phenotypic variation within individual species normally associated with much deeper evolutionary time scales. Though many variable traits found in domestic animals are the result of relatively recent human-mediated selection, uncertainty remains as to whether the modern ubiquity of long-standing variable traits such as coat color results from selection or drift, and whether the underlying alleles were present in the wild ancestor or appeared after domestication began. Here, through an investigation of sequence diversity at the porcine melanocortin receptor 1 (MC1R locus, we provide evidence that wild and domestic pig (Sus scrofa haplotypes from China and Europe are the result of strikingly different selection pressures, and that coat color variation is the result of intentional selection for alleles that appeared after the advent of domestication. Asian and European wild boar (evolutionarily distinct subspecies differed only by synonymous substitutions, demonstrating that camouflage coat color is maintained by purifying selection. In domestic pigs, however, each of nine unique mutations altered the amino acid sequence thus generating coat color diversity. Most domestic MC1R alleles differed by more than one mutation from the wild-type, implying a long history of strong positive selection for coat color variants, during which time humans have cherry-picked rare mutations that would be quickly eliminated in wild contexts. This pattern demonstrates that coat color phenotypes result from direct human selection and not via a simple relaxation of natural selective pressures.

  15. Production of multiple bacteriocins from a single locus by gastrointestinal strains of Lactobacillus salivarius.

    Science.gov (United States)

    O'Shea, Eileen F; O'Connor, Paula M; Raftis, Emma J; O'Toole, Paul W; Stanton, Catherine; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2011-12-01

    Bacteriocins produced by Lactobacillus salivarius isolates derived from a gastrointestinal origin have previously demonstrated efficacy for in vivo protection against Listeria monocytogenes infection. In this study, comparative genomic analysis was employed to investigate the intraspecies diversity of seven L. salivarius isolates of human and porcine intestinal origin, based on the genome of the well-characterized bacteriocin-producing strain L. salivarius UCC118. This revealed a highly conserved megaplasmid-borne gene cluster in these strains involved in the regulation and secretion of two-component class IIb bacteriocins. However, considerable intraspecific variation was observed in the structural genes encoding the bacteriocin peptides. They ranged from close relatives of abp118, such as salivaricin P, which differs by 2 amino acids, to completely novel bacteriocins, such as salivaricin T, which is characterized in this study. Salivaricin T inhibits closely related lactobacilli and bears little homology to previously characterized salivaricins. Interestingly, the two peptides responsible for salivaricin T activity, SalTα and SalTβ, share considerable identity with the component peptides of thermophilin 13, a bacteriocin produced by Streptococcus thermophilus. Furthermore, the salivaricin locus of strain DPC6488 also encodes an additional novel one-component class IId anti-listerial bacteriocin, salivaricin L. These findings suggest a high level of redundancy in the bacteriocins that can be produced by intestinal L. salivarius isolates using the same enzymatic production and export machinery. Such diversity may contribute to their ability to dominate and compete within the complex microbiota of the mammalian gut.

  16. In vivo genome editing of the albumin locus as a platform for protein replacement therapy

    Science.gov (United States)

    Sharma, Rajiv; Anguela, Xavier M.; Doyon, Yannick; Wechsler, Thomas; DeKelver, Russell C.; Sproul, Scott; Paschon, David E.; Miller, Jeffrey C.; Davidson, Robert J.; Shivak, David; Zhou, Shangzhen; Rieders, Julianne; Gregory, Philip D.; Holmes, Michael C.; Rebar, Edward J.

    2015-01-01

    Site-specific genome editing provides a promising approach for achieving long-term, stable therapeutic gene expression. Genome editing has been successfully applied in a variety of preclinical models, generally focused on targeting the diseased locus itself; however, limited targeting efficiency or insufficient expression from the endogenous promoter may impede the translation of these approaches, particularly if the desired editing event does not confer a selective growth advantage. Here we report a general strategy for liver-directed protein replacement therapies that addresses these issues: zinc finger nuclease (ZFN) –mediated site-specific integration of therapeutic transgenes within the albumin gene. By using adeno-associated viral (AAV) vector delivery in vivo, we achieved long-term expression of human factors VIII and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels. By using the same targeting reagents in wild-type mice, lysosomal enzymes were expressed that are deficient in Fabry and Gaucher diseases and in Hurler and Hunter syndromes. The establishment of a universal nuclease-based platform for secreted protein production would represent a critical advance in the development of safe, permanent, and functional cures for diverse genetic and nongenetic diseases. PMID:26297739

  17. Hypomutability in Fanconi anemia cells is associated with increased deletion frequency at the HPRT locus

    International Nuclear Information System (INIS)

    Papadopoulo, D.; Guillouf, C.; Moustacchi, E.; Mohrenweiser, H.

    1990-01-01

    Fanconi anemia (FA) is an inherited human disorder associated with a predisposition to cancer and characterized by anomalies in the processing of DNA cross-links and certain monoadducts. The authors reported previously that the frequency of psoralen-photoinduced mutations at the HPRT locus is lower in FA cells than in normal cells. This hypomutability is shown here to be associated with an increased frequency of deletions in the HPRT gene when either a mixture of cross-links and monoadducts or monoadducts alone are induced. Molecular analysis of mutants in the HPRT gene was carried out. In normal cells the majority of spontaneous and induced mutants are point mutations whereas in FA deletion mutations predominate. In that case a majority of mutants were found to lack individual exons or small clusters of exons whereas in normal cells large (complete or major gene loss) and small deletions are almost equally represented. Thus they propose that the FA defect lies in a mutagenic pathway that, in normal cells, involves by passing lesions and subsequent gap filling by a recombinational process during replication

  18. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus

    DEFF Research Database (Denmark)

    Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M

    2012-01-01

    (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly......The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor...... associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER...

  19. Induction of specific-locus mutations in the mouse by tritiated water

    International Nuclear Information System (INIS)

    Russell, W.L.; Cumming, R.B.; Kelly, E.M.; Phipps, E.L.

    1978-01-01

    The results reported are the first obtained on transmtted gene mutations induced by tritium in any form in any mammal. They are, therefore, of obvious practical importance in the estimaton of the possible biological hazards of man-made tritium in the environment. Male mice were injected intraperitoneally with either 0.75 or 0.50 mCi per gram of body weight of tritiated water. They were then used in our standard specific-locus mutation test in which the treated wild-type stock of mice is mated to a stock homozygous for seven recessive marker genes. Mutations at any of the seven loci are scored in the offspring. The earlier matings provided information on the mutation frequency in germ cells irradiated in postspermatogonial stages, and the later matings gave the mutation frequency in treated spermatogonia. The spermatogonia are the important cells so far as human risks are concerned, and the mouse results for this germ-cell stage yielded a relative biological effectiveness (RBE) of approximately 2 for tritiated water compared with low-dose-rate gamma irradiation. There are various uncertainties involved in arriving at this figure, and the difference between it and l is probably not statistically significant. However, for risk estimation, it seems prudent to use the RBE value of 2, which is, after all, the best point estimate computed from the present data

  20. Genotypic characterization by multi locus variable number of tandem repeats analysis international Bordetella pertussis vaccine strains

    Directory of Open Access Journals (Sweden)

    M. Fatah Moghadam

    2017-10-01

    Full Text Available Background: In 1930's first whole cell pertussis vaccines became available to the public heralding a dramatic success in overcoming the global burden of the disease. To date only a handful of B. pertussis strains have been used by international/local pertussis vaccine manufacturers. Inevitable well-documented genetic changes in the world population of this pathogen have prompted serious questions on suitability of traditional vaccine strains protect human against currently circulating wild isolates of Bordetella pertussis. Objective: Analyzing the genetic diversity within the most frequently-used vaccine strains of B. pertussis in the world Methods: A recently developed multi locus variable number of tandem repeats analysis (MLVA genotyping system along with a bioinforamtic piece of analysis was conducted on 11 strain / substrains of B137, B203 (10536, C393, Cs, E476, Tohama I, J445 (134, B202 and J446 (509 plus 2 sub-strains of 134 and 509 that are used at Razi institute for preparation of pertussis vaccine. In this study have used 6 individual loci of VNTR1, VNTR3a, VNTR3b, VNTR4, VNTR5 and VNTR6. Findings: Six distinct genotypes were recognized among the examined strains by comparing our data with the Dutch MLVA databank. These were all new and not reported before in the database. Conclusion: This observation reiterates on necessity for detection of predominant native strains to include in vaccine preparations suitable for different countries.

  1. Mutations in LOXHD1, a Recessive-Deafness Locus, Cause Dominant Late-Onset Fuchs Corneal Dystrophy

    Science.gov (United States)

    Riazuddin, S. Amer; Parker, David S.; McGlumphy, Elyse J.; Oh, Edwin C.; Iliff, Benjamin W.; Schmedt, Thore; Jurkunas, Ula; Schleif, Robert; Katsanis, Nicholas; Gottsch, John D.

    2012-01-01

    Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the protein's interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes. PMID:22341973

  2. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations

    DEFF Research Database (Denmark)

    Nielsen, Sofie V,; Stein, Amelie; Dinitzen, Alexander B.

    2017-01-01

    selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than...... and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases....

  3. Vocational interests of adolescents: relationships between self-esteem and locus of control.

    Science.gov (United States)

    Mullis, A K; Mullis, R L

    1997-12-01

    The purpose of this study was to examine relationships among scores on vocational interests, self-esteem, and locus of control for high school students. Grade and sex differences were also examined. 1364 high school students ranging in age from 14 to 19 years of age were administered the Coopersmith Self-esteem Inventory, Nowicki-Strickland Locus of Control Scale for Children, and the Strong-Campbell Interest Inventory. High school students with higher scores on self-esteem and showing an orientation toward internal locus of control expressed more interests in a variety of vocational themes than adolescents with lower scores on self-esteem and scores for external locus of control. Sex and grade differences in vocational interests of adolescents were also noted. The findings were discussed in light of theoretical and practical considerations.

  4. Analysis of an "off-ladder" allele at the Penta D short tandem repeat locus.

    Science.gov (United States)

    Yang, Y L; Wang, J G; Wang, D X; Zhang, W Y; Liu, X J; Cao, J; Yang, S L

    2015-11-25

    Kinship testing of a father and his son from Guangxi, China, the location of the Zhuang minority people, was performed using the PowerPlex® 18D System with a short tandem repeat typing kit. The results indicated that both the father and his son had an off-ladder allele at the Penta D locus, with a genetic size larger than that of the maximal standard allelic ladder. To further identify this locus, monogenic amplification, gene cloning, and genetic sequencing were performed. Sequencing analysis demonstrated that the fragment size of the Penta D-OL locus was 469 bp and the core sequence was [AAAGA]21, also called Penta D-21. The rare Penta D-21 allele was found to be distributed among the Zhuang population from the Guangxi Zhuang Autonomous Region of China; therefore, this study improved the range of DNA data available for this locus and enhanced our ability for individual identification of gene loci.

  5. RAS1, a quantitative trait locus for salt tolerance and ABA sensitivity in Arabidopsis

    KAUST Repository

    Ren, Zhonghai; Zheng, Zhimin; Chinnusamy, Viswanathan; Zhu, Jianhua; Cui, Xinping; Iida, Kei; Zhu, Jian-Kang

    2010-01-01

    Soil salinity limits agricultural production and is a major obstacle for feeding the growing world population. We used natural genetic variation in salt tolerance among different Arabidopsis accessions to map a major quantitative trait locus (QTL

  6. Relationship among prospective parents' locus of control, social desirability, and choice of psychoprophylaxis.

    Science.gov (United States)

    Windwer, C

    1977-01-01

    This study sought to determine if there is a relationship among locus of control, social desirability, and choice of psychoprophylaxis (PPM). It was hypothesized that internal locus of control and low social desirability would correlate significantly with the choice of PPM by husbands and wives; that externally controlled wives who participated in PPM would have more internally controlled husbands than externally controlled wives who participated in PPM would have more internally controlled husbands than externally controlled wives who did not participate; and that locus of control and social desirability, when taken together, would be better predictors of choice of PPM than either taken separately. Ninety-eight middle-class nulliparous couples, participant and non-participant, were studied in the seventh or eighth month of the wife's pregnancy. Rotter's I-E Scale and the Marlowe-Crowne Social Desirability Scale were used to measure locus of control and social desirability. Study findings did not support the hypotheses.

  7. Adult self-esteem and locus of control as a function of familial alcoholism and dysfunction.

    Science.gov (United States)

    Werner, L J; Broida, J P

    1991-05-01

    This study examines self-esteem and locus of control in adult children of alcoholics. We assessed these measures in 195 professional adults in relation to alcoholism and functioning in the family of origin. Although the presence of parental alcoholism was not a predictor of significant differences in adult self-esteem or locus of control, familial dysfunction was reflected in significant differences in self-esteem. This suggests that parental alcoholism does not necessarily result in personality differences in adult children.

  8. Relationship between Dental Anxiety and Health Locus of Control among Physiotherapy Students

    Directory of Open Access Journals (Sweden)

    Pooja Agarwal

    2013-01-01

    Materials & Method: A total of 152 students participated in the study. Dental anxiety was assessed using the 5 item Modified Dental Anxiety Scale (MDAS and Locus of Control was assessed using the 18 item Multidimensional Health Locus of Control (MHLC scale. Results: A Statistically significant positive correlation was found between the internal dimension of MHLC and dental anxiety. Conclusions: HLC was found to play an important role in predicting the dental anxiety among physiotherapy students.

  9. Health locus of control: Its relationship with medication adherence and medication wastage.

    Science.gov (United States)

    West, Lorna Marie; Borg Theuma, Ruth; Cordina, Maria

    2017-12-09

    Non-adherence is a significant factor contributing to medication wastage. Whilst there is some evidence on the influence of patients' health locus of control in relation to adherence, there has been little inquiry into its relationship with mediation wastage. To determine the relationship between medication adherence and health locus of control as well as medication wastage and health locus of control in patients with chronic conditions. Outpatients having a diagnosis of asthma, cardiovascular conditions, or diabetes participated in a cross-sectional study employing a self-administered questionnaire. The questionnaire determined presence of unused medication (wastage), adherence using 'Tool for Adherence Behaviour Screening' (TABS), and health locus of control using 'Multidimensional Health Locus of Control' (MHLC) scale Form C. Logistic regression was performed to ascertain the effects of MHLC and demographics in relation to adherence and wastage. MHLC beliefs were divided into 8 types of health locus of control. One-Way ANOVA was used to assess differences between conditions and belief types. P-values ≤ .05 were considered significant. There were 330 patients recruited (58% male; age, mean±(SD): 61 ± 15 years; 110 asthma, 110 cardiovascular, 110 diabetes). In terms of health locus of control, females had higher 'doctors' beliefs (p = .054) and significantly lower 'other people' beliefs (p = control. 'Yea-sayers' had the least presence of unused medication, followed by 'pure internal' believers. 'Pure powerful others external' had the highest presence of unused medication. Healthcare professionals should take into account patients' health locus of control beliefs whilst conducting an intervention with patients; this can impact positively medication adherence and minimisation of medication wastage. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. The effect of high and low assertiveness on locus of control and health problems.

    Science.gov (United States)

    Williams, J M; Stout, J K

    1985-03-01

    The effect of high and low assertiveness on locus of control and health problems was examined with 78 direct-service workers in mental health and mental retardation settings in northeastern Pennsylvania. The direct-service workers completed the Rathus (1973) Assertiveness Schedule, the Rotter (1966) Internal-External Locus of Control Scale, and a health-problems inventory. Highly assertive individuals were found to be more internally controlled and to experience fewer health problems than were individuals low in assertiveness.

  11. Efficient Recombinase-Mediated Cassette Exchange in hPSCs to Study the Hepatocyte Lineage Reveals AAVS1 Locus-Mediated Transgene Inhibition

    Directory of Open Access Journals (Sweden)

    Laura Ordovás

    2015-11-01

    Full Text Available Tools for rapid and efficient transgenesis in “safe harbor” loci in an isogenic context remain important to exploit the possibilities of human pluripotent stem cells (hPSCs. We created hPSC master cell lines suitable for FLPe recombinase-mediated cassette exchange (RMCE in the AAVS1 locus that allow generation of transgenic lines within 15 days with 100% efficiency and without random integrations. Using RMCE, we successfully incorporated several transgenes useful for lineage identification, cell toxicity studies, and gene overexpression to study the hepatocyte lineage. However, we observed unexpected and variable transgene expression inhibition in vitro, due to DNA methylation and other unknown mechanisms, both in undifferentiated hESC and differentiating hepatocytes. Therefore, the AAVS1 locus cannot be considered a universally safe harbor locus for reliable transgene expression in vitro, and using it for transgenesis in hPSC will require careful assessment of the function of individual transgenes.

  12. Prevalence of Porphyromonas gingivalis Four rag Locus Genotypes in Patients of Orthodontic Gingivitis and Periodontitis

    Science.gov (United States)

    Liu, Yi; Zhang, Yujie; Wang, Lili; Guo, Yang; Xiao, Shuiqing

    2013-01-01

    Porphyromonas gingivalis is considered as a major etiological agent in periodontal diseases and implied to result in gingival inflammation under orthodontic appliance. rag locus is a pathogenicity island found in Porphyromonas gingivalis. Four rag locus variants are different in pathogenicity of Porphyromonas gingivalis. Moreover, there are different racial and geographic differences in distribution of rag locus genotypes. In this study, we assessed the prevalence of Porphyromonas gingivalis and rag locus genotypes in 102 gingival crevicular fluid samples from 57 cases of gingivitis patients with orthodontic appliances, 25 cases of periodontitis patients and 20 cases of periodontally healthy people through a 16S rRNA-based PCR and a multiplex PCR. The correlations between Porphyromona.gingivalis/rag locus and clinical indices were analyzed. The prevalence of Porphyromonas gingivalis and rag locus genes in periodontitis group was the highest among three groups and higher in orthodontic gingivitis than healthy people (porthodontic gingivitis and mild-to-moderate periodontitis in Shandong. Porphyromonas.gingivalis carrying rag-1 has the strong virulence and could be associated with severe periodontitis. PMID:23593379

  13. Locus of control and peer relationships among Caucasian, Hispanic, Asian, and African American adolescents.

    Science.gov (United States)

    Kang, Hannah Soo; Chang, Kyle Edward; Chen, Chuansheng; Greenberger, Ellen

    2015-01-01

    Past research has shown that locus of control plays an important role in a wide range of behaviors, such as academic achievement and positive social behaviors. However, little is known about whether locus of control plays the same role in minority adolescents' peer relationships. The current study examined ethnic differences in the associations between locus of control and peer relationships in early adolescence using samples from the Early Childhood Longitudinal Study (ECLS-K: 5,612 Caucasian, 1,562 Hispanic, 507 Asian, and 908 African-American adolescents) and the National Education Longitudinal Study (NELS: 8,484 Caucasian, 1,604 Hispanic, and 860 Asian, and 1,228 African American adolescents). Gender was approximately evenly split in both samples. The results from the two datasets were highly consistent. Significant interactions between ethnicity and locus of control indicated that having a more internal locus of control was particularly important for Caucasian students' peer relationships (ECLS-K) and social status (NELS), but less so for Asian, Hispanic, and African American students. Our findings suggest that the role of locus of control in peer relationship is contingent upon culture.

  14. Social capital, political trust, and health locus of control: a population-based study.

    Science.gov (United States)

    Lindström, Martin

    2011-02-01

    To investigate the association between political trust in the Riksdag and lack of belief in the possibility to influence one's own health (external locus of control), taking horizontal trust into account. The 2008 public health survey in Skåne is a cross-sectional postal questionnaire study with a 55% participation rate. A random sample of 28,198 persons aged 18-80 years participated. Logistic regression models were used to investigate the associations between political trust in the Riksdag (an aspect of vertical trust) and lack of belief in the possibility to influence one's own health (external locus of control). The multiple regression analyses included age, country of birth, education, and horizontal trust in other people. A 33.7% of all men and 31.8% of all women lack internal locus of control. Low (external) health locus of control is more common in higher age groups, among people born outside Sweden, with lower education, low horizontal trust, low political trust, and no opinion concerning political trust. Respondents with not particularly strong political trust, no political trust at all and no opinion have significantly higher odds ratios of external locus of control throughout the multiple regression analyses. Low political trust in the Riksdag seems to be independently associated with external health locus of control.

  15. The stability of locus equation slopes across stop consonant voicing/aspiration

    Science.gov (United States)

    Sussman, Harvey M.; Modarresi, Golnaz

    2004-05-01

    The consistency of locus equation slopes as phonetic descriptors of stop place in CV sequences across voiced and voiceless aspirated stops was explored in the speech of five male speakers of American English and two male speakers of Persian. Using traditional locus equation measurement sites for F2 onsets, voiceless labial and coronal stops had significantly lower locus equation slopes relative to their voiced counterparts, whereas velars failed to show voicing differences. When locus equations were derived using F2 onsets for voiced stops that were measured closer to the stop release burst, comparable to the protocol for measuring voiceless aspirated stops, no significant effects of voicing/aspiration on locus equation slopes were observed. This methodological factor, rather than an underlying phonetic-based explanation, provides a reasonable account for the observed flatter locus equation slopes of voiceless labial and coronal stops relative to voiced cognates reported in previous studies [Molis et al., J. Acoust. Soc. Am. 95, 2925 (1994); O. Engstrand and B. Lindblom, PHONUM 4, 101-104]. [Work supported by NIH.

  16. Comparing health locus of control in patients with Spasmodic Dysphonia, Functional Dysphonia and Nonlaryngeal Dystonia.

    Science.gov (United States)

    Haselden, Karen; Powell, Theresa; Drinnan, Mike; Carding, Paul

    2009-11-01

    Locus of Control (LoC) refers to an individuals' perception of whether they are in control of life events. Health Locus of Control refers to whether someone feels they have influence over their health. Health Locus of Control has not been studied in any depth in voice-disordered patients. The objective of this study was to examine Health Locus of Control in three patient groups: (1) Spasmodic Dysphonia, (2) Functional Dysphonia and (3) a nondysphonic group with Nonlaryngeal Dystonia. LoC was measured and compared in a total of 57 patients using the Multidimensional Health Locus of Control Scales (diagnostic specific) Form C. Internal, Chance, and Powerful others LoC were measured and comparisons were made using one-way analysis of variance. Contrary to expectations Internal LoC was found to be significantly higher in the Functional Dysphonia group when compared to the other two groups. There was no significant difference between the groups in Chance or Powerful others LoC. The two organic groups, Spasmodic Dysphonia and Nonlaryngeal Dystonia, were more alike in Internal Health Locus of Control than the Functional Dysphonia group. The diagnostic nature of the groups was reflected in their LoC scores rather than their voice loss. These results contribute to the debate about the etiology of Spasmodic Dysphonia and will be of interest to those involved in the psychology of voice and those managing voice-disordered patients.

  17. Identification of a novel locus for a USH3 like syndrome combined with congenital cataract.

    Science.gov (United States)

    Dad, S; Østergaard, E; Thykjaer, T; Albrectsen, A; Ravn, K; Rosenberg, T; Møller, L B

    2010-10-01

    Usher syndrome (USH) is the most common genetic disease that causes both deafness and blindness. USH is divided into three types, USH1, USH2 and USH3, depending on the age of onset, the course of the disease, and on the degree of vestibular dysfunction. By homozygosity mapping of a consanguineous Danish family of Dutch descent, we have identified a novel locus for a rare USH3-like syndrome. The affected family members have a unique association of retinitis pigmentosa, progressive hearing impairment, vestibular dysfunction, and congenital cataract. The phenotype is similar, but not identical to that of USH3 patients, as congenital cataract has not been reported for USH3. By homozygosity mapping, we identified a 7.3 Mb locus on chromosome 15q22.2-23 with a maximum multipoint LOD score of 2.0. The locus partially overlaps with the USH1 locus, USH1H, a novel unnamed USH2 locus, and the non-syndromic deafness locus DFNB48. © 2010 John Wiley & Sons A/S.

  18. Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30 on rat chromosome 12: identification of fry as a candidate Mcs gene.

    Directory of Open Access Journals (Sweden)

    Xuefeng Ren

    Full Text Available Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop and susceptible Fischer 344 (F344 strains, we mapped a novel mammary carcinoma susceptibility (Mcs30 locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker. The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs, one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.

  19. Heavy metals in locus ceruleus and motor neurons in motor neuron disease.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2013-12-12

    The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.

  20. Heavy metals in locus ceruleus and motor neurons in motor neuron disease

    Science.gov (United States)

    2013-01-01

    Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

  1. The 4q27 locus and prostate cancer risk

    International Nuclear Information System (INIS)

    Tindall, Elizabeth A; Hoang, Hoa N; Southey, Melissa C; English, Dallas R; Hopper, John L; Giles, Graham G; Severi, Gianluca; Hayes, Vanessa M

    2010-01-01

    Chronic inflammation is considered to be implicated in the development of prostate cancer. In this study we are the first to investigate a potential association between variants in an autoimmune related region on chromosome 4q27 and prostate cancer risk. This region harbors two cytokine genes IL-2 and the recently described IL-21. We genotyped six variants previously associated with autoimmune disease (namely rs13151961, rs13119723, rs17388568, rs3136534, rs6822844 and rs6840978) and one functional IL-2 promoter variant (rs2069762) for possible association with prostate cancer risk using the Australian Risk Factors for Prostate Cancer case-control Study. Overall, our results do not support an association between the seven variants at position 4q27 and prostate cancer risk. Per allele odds ratios (ORs) were not significantly different from 1 (all P-values = 0.06). However, we found suggestive evidence for a significant association between the presence of the rs13119723 variant (located in a protein of unknown function) and men with a family history of prostate cancer in first-degree relatives (P-value for interaction 0.02). The per allele OR associated with this variant was significantly higher than 1 (2.37; 95% C.I. = 1.01-5.57). We suggest that genetic variation within the chromosome 4q27 locus might be associated with prostate cancer susceptibility in men with a family history of the disease. Furthermore, our study alludes to a potential role of unknown protein KIAA1109 in conferring this risk

  2. Variants at the 9p21 locus and melanoma risk

    International Nuclear Information System (INIS)

    Maccioni, Livia; Rachakonda, Panduranga Sivaramakrishna; Bermejo, Justo Lorenzo; Planelles, Dolores; Requena, Celia; Hemminki, Kari; Nagore, Eduardo; Kumar, Rajiv

    2013-01-01

    The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3’ UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A–allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes

  3. Genomic Locus Modulating IOP in the BXD RI Mouse Strains

    Directory of Open Access Journals (Sweden)

    Rebecca King

    2018-05-01

    Full Text Available Intraocular pressure (IOP is the primary risk factor for developing glaucoma, yet little is known about the contribution of genomic background to IOP regulation. The present study leverages an array of systems genetics tools to study genomic factors modulating normal IOP in the mouse. The BXD recombinant inbred (RI strain set was used to identify genomic loci modulating IOP. We measured the IOP in a total of 506 eyes from 38 different strains. Strain averages were subjected to conventional quantitative trait analysis by means of composite interval mapping. Candidate genes were defined, and immunohistochemistry and quantitative PCR (qPCR were used for validation. Of the 38 BXD strains examined the mean IOP ranged from a low of 13.2mmHg to a high of 17.1mmHg. The means for each strain were used to calculate a genome wide interval map. One significant quantitative trait locus (QTL was found on Chr.8 (96 to 103 Mb. Within this 7 Mb region only 4 annotated genes were found: Gm15679, Cdh8, Cdh11 and Gm8730. Only two genes (Cdh8 and Cdh11 were candidates for modulating IOP based on the presence of non-synonymous SNPs. Further examination using SIFT (Sorting Intolerant From Tolerant analysis revealed that the SNPs in Cdh8 (Cadherin 8 were predicted to not change protein function; while the SNPs in Cdh11 (Cadherin 11 would not be tolerated, affecting protein function. Furthermore, immunohistochemistry demonstrated that CDH11 is expressed in the trabecular meshwork of the mouse. We have examined the genomic regulation of IOP in the BXD RI strain set and found one significant QTL on Chr. 8. Within this QTL, there is one good candidate gene, Cdh11.

  4. Locus-specific ribosomal RNA gene silencing in nucleolar dominance.

    Directory of Open Access Journals (Sweden)

    Michelle S Lewis

    2007-08-01

    Full Text Available The silencing of one parental set of rRNA genes in a genetic hybrid is an epigenetic phenomenon known as nucleolar dominance. We showed previously that silencing is restricted to the nucleolus organizer regions (NORs, the loci where rRNA genes are tandemly arrayed, and does not spread to or from neighboring protein-coding genes. One hypothesis is that nucleolar dominance is the net result of hundreds of silencing events acting one rRNA gene at a time. A prediction of this hypothesis is that rRNA gene silencing should occur independent of chromosomal location. An alternative hypothesis is that the regulatory unit in nucleolar dominance is the NOR, rather than each individual rRNA gene, in which case NOR localization may be essential for rRNA gene silencing. To test these alternative hypotheses, we examined the fates of rRNA transgenes integrated at ectopic locations. The transgenes were accurately transcribed in all independent transgenic Arabidopsis thaliana lines tested, indicating that NOR localization is not required for rRNA gene expression. Upon crossing the transgenic A. thaliana lines as ovule parents with A. lyrata to form F1 hybrids, a new system for the study of nucleolar dominance, the endogenous rRNA genes located within the A. thaliana NORs are silenced. However, rRNA transgenes escaped silencing in multiple independent hybrids. Collectively, our data suggest that rRNA gene activation can occur in a gene-autonomous fashion, independent of chromosomal location, whereas rRNA gene silencing in nucleolar dominance is locus-dependent.

  5. ANTXR2 is a potential causative gene in the genome-wide association study of the blood pressure locus 4q21.

    Science.gov (United States)

    Park, So Yon; Lee, Hyeon-Ju; Ji, Su-Min; Kim, Marina E; Jigden, Baigalmaa; Lim, Ji Eun; Oh, Bermseok

    2014-09-01

    Hypertension is the most prevalent cardiovascular disease worldwide, but its genetic basis is poorly understood. Recently, genome-wide association studies identified 33 genetic loci that are associated with blood pressure. However, it has been difficult to determine whether these loci are causative owing to the lack of functional analyses. Of these 33 genome-wide association studies (GWAS) loci, the 4q21 locus, known as the fibroblast growth factor 5 (FGF5) locus, has been linked to blood pressure in Asians and Europeans. Using a mouse model, we aimed to identify a causative gene in the 4q21 locus, in which four genes (anthrax toxin receptor 2 (ANTXR2), PR domain-containing 8 (PRDM8), FGF5 and chromosome 4 open reading frame 22 (C4orf22)) were near the lead single-nucleotide polymorphism (rs16998073). Initially, we examined Fgf5 gene by measuring blood pressure in Fgf5-knockout mice. However, blood pressure did not differ between Fgf5 knockout and wild-type mice. Therefore, the other candidate genes were studied by in vivo small interfering RNA (siRNA) silencing in mice. Antxr2 siRNA was pretreated with polyethylenimine and injected into mouse tail veins, causing a significant decrease in Antxr2 mRNA by 22% in the heart. Moreover, blood pressure measured under anesthesia in Antxr2 siRNA-injected mice rose significantly compared with that of the controls. These results suggest that ANTXR2 is a causative gene in the human 4q21 GWAS-blood pressure locus. Additional functional studies of ANTXR2 in blood pressure may identify a novel genetic pathway, thus increasing our understanding of the etiology of essential hypertension.

  6. Effectiveness of teaching cognitive-behavioral techniques on locus of control in hemodialysis patients.

    Science.gov (United States)

    Mehrtak, Mohammad; Habibzadeh, Shahram; Farzaneh, Esmaeil; Rjaei-Khiavi, Abdollah

    2017-10-01

    Many of the cognitive behavioral models and therapeutic protocols developed so far for psychological disorders and chronic diseases have proved effective through clinical research. This study aimed to determine the effectiveness of teaching cognitive-behavioral techniques on locus of control in hemodialysis patients. This controlled clinical trial study was conducted in 2015 with 76 patients selected by census and treated with a hemodialysis machine in the dialysis department of Vali-Asr Hospital in the city of Meshkinshahr. A total of four patients were excluded because of their critical conditions while the rest, who were recruited, were randomly divided into two equal groups of 36 patients as the intervention and control groups. First, the locus of control was measured in both groups through a pretest, and cognitive-behavioral techniques were then taught to the intervention group during eight 45 to 90-minute sessions. The locus of control in patients of both groups was finally re-measured through a posttest. Data were collected using Rotter's Locus of Control Inventory. The Wilcoxon test and Mann-Whitney U test were respectively used in SPSS18 for data analysis. In the pretest and posttest stages respectively, 4.8% and 14.3% of samples in the control group as well as 14.3% and 33.3% of samples in the intervention group enjoyed internal locus of control. The difference between the pretest and posttest scores of internal locus of control in the intervention group was significant (p=0.004), which indicates the positive effect of cognitive-behavioral psychotherapeutic intervention on internalization of locus of control in this group. Given the external locus of control in most of the study patients and also the positive significant effect of cognitive-behavioral psychotherapy on internalization of locus of control in this group of patients, it appears necessary to have a psychology resident present in the hemodialysis department to teach the necessary cognitive

  7. Assay for mutagenesis in heterozygous diploid human lymphoblasts

    Science.gov (United States)

    Skopek, Thomas R.; Liber, Howard L.; Penman, Bruce W.; Thilly, William G.; Hoppe, IV, Henry

    1981-01-01

    An assay is disclosed for determining mutagenic damage caused by the administration of a known or suspected mutagen to diploid human lymphoblastoid cell lines. The gene locus employed for this assay is the gene for thymidine kinase, uridine kinase, or cytidine deaminase. Since human lymphoblastoid cells contain two genes for these enzymes, heterozygotes of human lymphoblastoid cells are used in this assay.

  8. Genetic mapping of the female mimic morph locus in the ruff

    Science.gov (United States)

    2013-01-01

    Background Ruffs (Aves: Philomachus pugnax) possess a genetic polymorphism for male mating behaviour resulting in three permanent alternative male reproductive morphs: (i) territorial ‘Independents’, (ii) non-territorial ‘Satellites’, and (iii) female-mimicking ‘Faeders’. Development into independent or satellite morphs has previously been shown to be due to a single-locus, two-allele autosomal Mendelian mode of inheritance at the Satellite locus. Here, we use linkage analysis to map the chromosomal location of the Faeder locus, which controls development into the Faeder morph, and draw further conclusions about candidate genes, assuming shared synteny with other birds. Results Segregation data on the Faeder locus were obtained from captive-bred pedigrees comprising 64 multi-generation families (N = 381). There was no evidence that the Faeder locus was linked to the Satellite locus, but it was linked with microsatellite marker Ppu020. Comparative mapping of ruff microsatellite markers against the chicken (Gallus gallus) and zebra finch (Taeniopygia guttata) genomes places the Ppu020 and Faeder loci on a region of chromosome 11 that includes the Melanocortin-1 receptor (MC1R) gene, which regulates colour polymorphisms in numerous birds and other vertebrates. Melanin-based colouration varies with life-history strategies in ruffs and other species, thus the MC1R gene is a strong candidate to play a role in alternative male morph determination. Conclusion Two unlinked loci appear to control behavioural development in ruffs. The Faeder locus is linked to Ppu020, which, assuming synteny, is located on avian chromosome 11. MC1R is a candidate gene involved in alternative male morph determination in ruffs. PMID:24256185

  9. Identification of a fourth locus (EVR4) for familial exudative vitreoretinopathy (FEVR).

    Science.gov (United States)

    Toomes, Carmel; Downey, Louise M; Bottomley, Helen M; Scott, Sheila; Woodruff, Geoffrey; Trembath, Richard C; Inglehearn, Chris F

    2004-01-15

    Familial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous inherited blinding disorder of the retinal vascular system. To date three loci have been mapped: EVR1 on chromosome 11q, EVR2 on chromosome Xp, and EVR3 on chromosome 11p. The gene underlying EVR3 remains unidentified whilst the EVR2 gene, which encodes the Norrie disease protein (NDP), was identified over a decade ago. More recently, FZD4, the gene that encodes the Wnt receptor Frizzled-4, was identified as the mutated gene at the EVR1 locus. The purpose of this study was to screen FZD4 in a large family previously proven to be linked to the EVR1 locus. PCR products were generated using genomic DNA from affected family members with primers designed to amplify the coding sequence of FZD4. The PCR products were screened for mutations by direct sequencing. Genotyping was performed in all available family members using fluorescently labeled microsatellite markers from chromosome 11q. Sequencing of the EVR1 gene, FZD4, in this family identified no mutation. To investigate this family further we performed high-resolution genotyping with markers spanning chromosome 11q. Haplotype analysis excluded FZD4 as the mutated gene in this family and identified a candidate region approximately 10 cM centromeric to EVR1. This new FEVR locus is flanked by markers D11S1368 (centromeric) and D11S937 (telomeric) and spans approximately 15 cM. High-resolution genotyping and haplotype analysis excluded FZD4 as the defective gene in a family previously linked to the EVR1 locus. The results indicate that the gene mutated in this family lies centromeric to the EVR1 gene, FZD4, and is also genetically distinct from the EVR3 locus. This new locus has been designated EVR4 and is the fourth FEVR locus to be described.

  10. Maxwell Strata and Cut Locus in the Sub-Riemannian Problem on the Engel Group

    Science.gov (United States)

    Ardentov, Andrei A.; Sachkov, Yuri L.

    2017-12-01

    We consider the nilpotent left-invariant sub-Riemannian structure on the Engel group. This structure gives a fundamental local approximation of a generic rank 2 sub-Riemannian structure on a 4-manifold near a generic point (in particular, of the kinematic models of a car with a trailer). On the other hand, this is the simplest sub-Riemannian structure of step three. We describe the global structure of the cut locus (the set of points where geodesics lose their global optimality), the Maxwell set (the set of points that admit more than one minimizer), and the intersection of the cut locus with the caustic (the set of conjugate points along all geodesics). The group of symmetries of the cut locus is described: it is generated by a one-parameter group of dilations R+ and a discrete group of reflections Z2 × Z2 × Z2. The cut locus admits a stratification with 6 three-dimensional strata, 12 two-dimensional strata, and 2 one-dimensional strata. Three-dimensional strata of the cut locus are Maxwell strata of multiplicity 2 (for each point there are 2 minimizers). Two-dimensional strata of the cut locus consist of conjugate points. Finally, one-dimensional strata are Maxwell strata of infinite multiplicity, they consist of conjugate points as well. Projections of sub-Riemannian geodesics to the 2-dimensional plane of the distribution are Euler elasticae. For each point of the cut locus, we describe the Euler elasticae corresponding to minimizers coming to this point. Finally, we describe the structure of the optimal synthesis, i. e., the set of minimizers for each terminal point in the Engel group.

  11. Detailed mapping of a resistance locus against Fusarium wilt in cultivated eggplant (Solanum melongena).

    Science.gov (United States)

    Miyatake, Koji; Saito, Takeo; Negoro, Satomi; Yamaguchi, Hirotaka; Nunome, Tsukasa; Ohyama, Akio; Fukuoka, Hiroyuki

    2016-02-01

    This is the first report on genetic mapping of a resistance locus against Fusarium wilt caused by the plant pathogen Fusarium oxysporum f. sp. melongenae in cultivated eggplant. Fusarium wilt, caused by the plant pathogen Fusarium oxysporum f. sp. melongenae, is a major soil-borne disease threatening stable production in eggplant (Solanum melongena). Although three eggplant germplasms, LS1934, LS174, and LS2436, are known to be highly resistant to the pathogen, their resistance loci have not been mapped. In this study, we performed quantitative trait locus analyses in F2:3 populations and detected a resistance locus, FM1, at the end of chromosome 2, with two alleles, Fm1(L) and Fm1(E), in the F2 populations LWF2 [LS1934 × WCGR112-8 (susceptible)] and EWF2 [EPL-1 (derived from LS174) × WCGR112-8], respectively. The percentage of phenotypic variance explained by Fm1(L) derived from LS1934 was 75.0% [Logarithm of the odds (LOD) = 29.3], and that explained by Fm1(E) derived from EPL-1 was 92.2% (LOD = 65.8). Using backcrossed inbred lines, we mapped FM1 between two simple sequence repeat markers located ~4.881 cM apart from each other. Comparing the location of the above locus to those of previously reported ones, the resistance locus Rfo-sa1 from an eggplant ally (Solanum aethiopicum gr. Gilo) was mapped very close to FM1, whereas another resistance locus, from LS2436, was mapped to the middle of chromosome 4. This is the first report of mapping of a Fusarium resistance locus in cultivated eggplant. The availability of resistance-linked markers will enable the application of marker-assisted selection to overcome problems posed by self-incompatibility and introduction of negative traits because of linkage drag, and will lead to clear understanding of genetic mechanism of Fusarium resistance.

  12. Participation of locus coeruleus in breathing control in female rats.

    Science.gov (United States)

    de Carvalho, Débora; Patrone, Luis Gustavo A; Marques, Danuzia A; Vicente, Mariane C; Szawka, Raphael E; Anselmo-Franci, Janete A; Bícego, Kênia C; Gargaglioni, Luciane H

    2017-11-01

    Several evidences indicate that the locus coeruleus (LC) is involved in central chemoreception responding to CO 2 /pH and displaying a high percentage of chemosensitive neurons (>80%). However, there are no studies about the LC-mediated hypercapnic ventilation performed in females. Therefore, we assessed the role of noradrenergic LC neurons in non-ovariectomized (NOVX), ovariectomized (OVX) and estradiol (E2)-treated ovariectomized (OVX+E2) rats in respiratory response to hypercapnia, using a 6-hydroxydopamine (6-OHDA) - lesion model. A reduction in the number of tyrosine hydroxylase (TH) immunoreactive neurons (51-90% in 3 animals of NOVX group, 20-42% of lesion in 5 animals of NOVX females, 61.3% for OVX and 62.6% for OVX+E2 group) was observed seven days after microinjection of 6-OHDA in the LC. The chemical lesion of the LC resulted in decreased respiratory frequency under normocapnic conditions in OVX and OVX+E2 group. Hypercapnia increased ventilation in all groups as consequence of increases in respiratory frequency (fR) and tidal volume (V T ). Nevertheless, the hypercapnic ventilatory response was significantly decreased in 6-OHDA-NOVX>50% rats compared with SHAM-NOVX group and with females that had 20-42% of LC lesion. In OVX and OVX+E2 lesioned groups, no difference in CO 2 ventilatory response was observed when compared to SHAM-OVX and SHAM-OVX+E2 groups, respectively. Neither basal body temperature (Tb) nor Tb reduction in response to hypercapnia were affected by E2 treatment, ovariectomy or LC lesion. Thus, our data show that LC noradrenergic neurons seem to exert an excitatory role on the hypercapnic ventilatory response in female rats, as evidenced by the results in NOVX animals with LC lesioned more than 50%; however, this modulation is not observed in OVX and OVX+E2 rats. In addition, LC noradrenergic neurons of OVX females seem to provide a tonic excitatory drive to maintain breathing frequency in normocapnia, and this response may not to be

  13. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management

    NARCIS (Netherlands)

    D. Ramsoekh (Dewkoemar); A. Wagner (Anja); M.E. van Leerdam (Monique); D. Dooijes (Dennis); C.M.J. Tops (Carli); E.W. Steyerberg (Ewout); E.J. Kuipers (Ernst)

    2009-01-01

    textabstractBackground: Lynch syndrome (LS) is associated with a high risk for colorectal cancer (CRC) and extracolonic malignancies, such as endometrial carcinoma (EC). The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of

  14. Confirmatory factor analysis and invariance testing between Blacks and Whites of the Multidimensional Health Locus of Control scale.

    Science.gov (United States)

    LaNoue, Marianna; Harvey, Abby; Mautner, Dawn; Ku, Bon; Scott, Kevin

    2015-07-01

    The factor structure of the Multidimensional Health Locus of Control scale remains in question. Additionally, research on health belief differences between Black and White respondents suggests that the Multidimensional Health Locus of Control scale may not be invariant. We reviewed the literature regarding the latent variable structure of the Multidimensional Health Locus of Control scale, used confirmatory factor analysis to confirm the three-factor structure of the Multidimensional Health Locus of Control, and analyzed between-group differences in the Multidimensional Health Locus of Control structure and means across Black and White respondents. Our results indicate differences in means and structure, indicating more research is needed to inform decisions regarding whether and how to deploy the Multidimensional Health Locus of Control appropriately.

  15. The Impact of Locus of Control and Controlling Language on Psychological Reactance and Ad Effectiveness in Health Communication.

    Science.gov (United States)

    Xu, Jie

    2017-12-01

    Based on two theoretical models-psychological reactance theory (PRT) and locus of control-this study examines the individual and joint effects of locus of control and controlling language on young adults' information processing. Two experimental studies on anti-driving-after-drinking (anti-DAD) and antismoking public service announcements (PSAs) were conducted that were conceptual replications of each other. Both studies afforded evidence that those with external locus of control were more involved in risky behaviors. There was a consistent interaction between locus of control and controlling language, such that those with internal locus of control were more sensitive to this message feature compared to those with external locus of control. Controlling language was found to increase reactance. The theoretical and managerial implications for health communication are elaborated. Limitations and directions for future research are also outlined.

  16. The influence of U-2 fraction of a tortoise spleen extract on the formation of ectopic locus of haemopoiesis

    International Nuclear Information System (INIS)

    Turdyev, A.A.; Prus, E.K.; Basova, A.R.

    1990-01-01

    The implantation of a bone marrow fragment of intact mouse donors below the kidney capsule of irradiated (7 Gy) recipients leads to the formation of the haemopoiesis locus that somewhat exceeds, by mass and cellularity, the new-formed locus of control animals. The U-2 fraction of a tortoise spleen extract administered to recipients irradiated with the same dose increases the mass and cellularity of the haemopoiesis locus by 2.2 and 4.9 times respectively

  17. Linkage disequilibrium at the APA insecticidal seed protein locus of common bean (Phaseolus vulgaris L.).

    Science.gov (United States)

    Blair, Matthew W; Prieto, Sergio; Díaz, Lucy M; Buendía, Héctor F; Cardona, César

    2010-04-29

    An interesting seed protein family with a role in preventing insect herbivory is the multi-gene, APA family encoding the alpha-amylase inhibitor, phytohemagglutinin and arcelin proteins of common bean (Phaseolus vulgaris). Variability for this gene family exists and has been exploited to breed for insect resistance. For example, the arcelin locus has been successfully transferred from wild to cultivated common bean genotypes to provide resistance against the bruchid species Zabrotes subfasciatus although the process has been hampered by a lack of genetic tools for and understanding about the locus. In this study, we analyzed linkage disequilibrium (LD) between microsatellite markers at the APA locus and bruchid resistance in a germplasm survey of 105 resistant and susceptible genotypes and compared this with LD in other parts of the genome. Microsatellite allele diversity was found to vary with each of the eight APA-linked markers analyzed, and two markers within the APA locus were found to be diagnostic for bruchid resistance or susceptibility and for the different arcelin alleles inherited from the wild accessions. Arc1 was found to provide higher levels of resistance than Arc5 and the markers in the APA locus were highly associated with resistance showing that introgression of this gene-family from wild beans provides resistance in cultivated beans. LD around the APA locus was found to be intermediate compared to other regions of the genome and the highest LD was found within the APA locus itself for example between the markers PV-atct001 and PV-ag004. We found the APA locus to be an important genetic determinant of bruchid resistance and also found that LD existed mostly within the APA locus but not beyond it. Moderate LD was also found for some other regions of the genome perhaps related to domestication genes. The LD pattern may reflect the introgression of arcelin from the wild into the cultivated background through breeding. LD and association studies for

  18. Composición del locus de control en dos ciudades latinoamericanas

    Directory of Open Access Journals (Sweden)

    Jesús Francisco Laborín Álvarez

    2008-01-01

    Full Text Available El locus de control es un rasgo de personalidad vinculado con la atribución que hacen los individuos acerca de sus éxitos y fracasos. Los estudios en diferentes naciones y sociedades han demostrado que existen características generales y particulares respecto a la percepción de control y donde la cultura juega un papel importante. Se partió del objetivo de conocer la composición factorial del locus de control en dos poblaciones, Hermosillo, Sonora (México (n=600 y João Pessoa, Paraíba (Brasil (n=600; y establecer las diferencias en cuanto a dicho constructo en ambas poblaciones con respecto a las variables atributivas: edad, escolaridad, ocupación y ciudad. Los resultados revelan tres dimensiones comunes a las dos poblaciones: locus de control interno, locus de control afiliativo y locus de control externo. Los datos en general hacen ver que las muestras poblacionales de las ciudades hacen juicios de control en relación a los esfuerzos y el trabajo personal, en la afiliación a colectivos y grupos de interés como los fundamentos de explicación para éxitos y fracasos.

  19. Locus specificity in the mutability of mouse lymphoma strain LY-S

    International Nuclear Information System (INIS)

    Evans, H.H.; Mencl, J.; Horng, M.F.

    1985-01-01

    Mouse lymphoma L5178Y strains, LY-R and LY-S, are closely related but differ in their sensitivity to the lethal effects of radiation and various chemicals. Strain LY-S was originally isolated in 1961 following a spontaneous change in the sensitivity of cultured LY-R cells to ionizing radiation. The authors previously reported that, although strain LY-S is more sensitive to the lethal effects of ionizing radiation and alkylating agents than strain LY-R, it is markedly less mutable than strain LY-R at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus. The isolated sublines of strains LY-R and LY-S which are heterozygous at the thymidine kinase (TK) locus. The LY-S TK+/- heterozygote, like its TK+/+ parent, is more sensitive to the lethal effects of ionizing radiation and alkylating agents and less mutable at the HGPRT locus by these agents than the LY-R TK+/- heterozygote. However, the LY-S heterozygote is 100 times more mutable by these agents at the TK locus than at the HGRT locus. In contrast to LY-R, the majority of the spontaneous and induced LY-S TK-/- mutants form small colonies in the presence of trifluorothymidine, indicating that in the LY-S heterozygote, the inactivation of the TK gene is accompanied by damage to, or rearrangement of neighboring genes

  20. Chronically ill patients’ expectations of therapeutic education and their health locus of control

    Directory of Open Access Journals (Sweden)

    Małgorzata Anna Basińska

    2015-12-01

    Full Text Available Background Beliefs as cognitive components of personality indicate what we consider as true or false and help us to answer questions concerning others, the world surrounding us and situations that we encounter. Beliefs about the health locus of control and their relations with expectations pertaining to therapeutic education seem to be of vital importance in the case of occurrence of a chronic illness. The aim of this paper is to verify whether expectations concerning therapeutic education in chronically ill patients demonstrate a relation with beliefs about the health locus of control and whether they vary according to gender, age and health, and to present the results of research that applies the Polish OE-15 scale for the evaluation of therapeutic education expectations depending on the health condition. Participants and procedure Two hundred and ninety-one persons were examined, including 180 patients and 111 healthy controls (the control group, 187 women and 104 men. The average age of subjects was 45.71 (SD = 13.51 years, ranging from 21 to 80 years. The OE-15 Therapeutic Education Expectations Scale and the Multidimensional Health Locus of Control Scale in versions relevant for patients and healthy controls as well as demographics were used. Results Age, gender and beliefs about the health locus of control are related to expectations of therapeutic education. Conclusions When providing therapeutic education for chronically ill patients, one should assess their expectations and pay attention to patients’ beliefs about the health locus of control.

  1. [Locus of control and self-concept in interpersonal conflict resolution approaches].

    Science.gov (United States)

    Hisli Sahin, Nesrin; Basim, H Nejat; Cetin, Fatih

    2009-01-01

    The purpose of this study was to investigate the relationship between self-concept and locus of control in interpersonal conflict resolution approaches and to determine the predictors of conflict resolution approach choices. The study included 345 students aged between 18 and 28 years that were studying at universities in Ankara. Data were collected using the Interpersonal Conflict Resolution Approaches Scale to measure conflict resolution approaches, the Social Comparison Scale to measure self-concept, and the Internal-External Locus of Control Scale to measure locus of control. It was observed that confrontation approach to interpersonal conflict was predicted by self-concept (beta = 0.396, P resolution approaches. In addition to these findings, it was observed that females used self-disclosure (beta = -0.163, P resolution processes. Self-concept and locus of control were related to the behaviors adopted in the interpersonal conflict resolution process. Individuals with a positive self-concept and an internal locus of control adopted solutions to interpersonal conflict resolution that were more effective and constructive.

  2. Comparing Locus of Control, Assertiveness and General Health among Young Drug Addicts in Iran

    Directory of Open Access Journals (Sweden)

    Shahriar Shahidi

    2009-04-01

    Full Text Available "n "nObjective:The aim of this research was to compare the characteristics of assertiveness, locus of control and general health among young drug dependent patients in Iran. "n "nMethods: Three groups of Iranians: were choosed. The first group included drug dependent patients who had volunteered for treatment and had registered in the local Welfare Organization; the second group included dependent patients who were in the prison; and the third group held nondependent patients. All the participants were male and were matched for age and educational level . The following instruments were used in the present study: locus of control  uestionnaire , Assertiveness Scale and the General Health Questionnaire, GHQ. "n "nResults: The results of the present research showed that there were significant differences among the three groups in ssertiveness, locus of control and GHQ scores. It was found that participants in the non addictive group were more assertive and more internal in their locus of control and had higher GHQ scores than the other two groups. The participants in the prison group reported less assertiveness and lower GHQ scores than the non addictive group ; and their locus of control was more external. Conclusion: "n The results this study may be useful in terms of possible strategies for changing an attributive style in young adults in the framework of psychotherapy

  3. LocusTrack: Integrated visualization of GWAS results and genomic annotation.

    Science.gov (United States)

    Cuellar-Partida, Gabriel; Renteria, Miguel E; MacGregor, Stuart

    2015-01-01

    Genome-wide association studies (GWAS) are an important tool for the mapping of complex traits and diseases. Visual inspection of genomic annotations may be used to generate insights into the biological mechanisms underlying GWAS-identified loci. We developed LocusTrack, a web-based application that annotates and creates plots of regional GWAS results and incorporates user-specified tracks that display annotations such as linkage disequilibrium (LD), phylogenetic conservation, chromatin state, and other genomic and regulatory elements. Currently, LocusTrack can integrate annotation tracks from the UCSC genome-browser as well as from any tracks provided by the user. LocusTrack is an easy-to-use application and can be accessed at the following URL: http://gump.qimr.edu.au/general/gabrieC/LocusTrack/. Users can upload and manage GWAS results and select from and/or provide annotation tracks using simple and intuitive menus. LocusTrack scripts and associated data can be downloaded from the website and run locally.

  4. Does cognitive training improve internal locus of control among older adults?

    Science.gov (United States)

    Wolinsky, Fredric D; Vander Weg, Mark W; Martin, René; Unverzagt, Frederick W; Willis, Sherry L; Marsiske, Michael; Rebok, George W; Morris, John N; Ball, Karlene K; Tennstedt, Sharon L

    2010-09-01

    We evaluated the effect of cognitive training among 1,534 participants in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) randomized controlled trial (RCT) on 5-year improvements in 3 cognitive-specific measures of locus of control-internal, chance, and powerful others. ACTIVE was a multisite RCT (age > or = 65), with 4 groups (memory, reasoning, speed of processing, and no-contact control). Complete 5-year follow-up data were available for 1,534 (55%) of the 2,802 participants. A propensity score model was used to adjust for potential attrition bias. Clinically important improvements (and decrements) in the cognitive-specific locus of control scale scores were defined as greater than or equal to 0.5 SD (medium) and greater than or equal to 1.0 SD (large). Multinomial logistic regression was used to simultaneously contrast those who improved and those who declined with those whose locus of control scale score was unchanged. Statistically significant effects reflecting medium-sized (> or = 0.5 SD) improvements in internal locus of control between baseline and the 5-year follow-up were found for the reasoning and speed of processing intervention groups who were 76% (p control group. No improvement effects were found on the chance or powerful others locus of control measures or for the memory intervention group. Cognitive training that targets reasoning and speed of processing can improve the cognitive-specific sense of personal control over one's life in older adults.

  5. Root locus analysis and design of the adaptation process in active noise control.

    Science.gov (United States)

    Tabatabaei Ardekani, Iman; Abdulla, Waleed H

    2012-10-01

    This paper applies root locus theory to develop a graphical tool for the analysis and design of adaptive active noise control systems. It is shown that the poles of the adaptation process performed in these systems move on typical trajectories in the z-plane as the adaptation step-size varies. Based on this finding, the dominant root of the adaptation process and its trajectory can be determined. The first contribution of this paper is formulating parameters of the adaptation process root locus. The next contribution is introducing a mechanism for modifying the trajectory of the dominant root in the root locus. This mechanism creates a single open loop zero in the original root locus. It is shown that appropriate localization of this zero can cause the dominant root of the locus to be pushed toward the origin, and thereby the adaptation process becomes faster. The validity of the theoretical findings is confirmed in an experimental setup which is implemented using real-time multi-threading and multi-core processing techniques.

  6. Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.

    Science.gov (United States)

    Patten, M M

    2014-11-01

    Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture. © 2014 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

  7. PENGARUH TEKANAN ANGGARAN WAKTU, LOCUS OF CONTROL DAN KOMITMEN PROFESIONAL PADA PERILAKU PENURUNAN KUALITAS AUDIT

    Directory of Open Access Journals (Sweden)

    NI Wayan Wiwin Intan Wintari

    2016-02-01

    Full Text Available The Impact of Time Budget Pressure, Locus of Control and Professional Commitment on the Reduction of Audit Quality Behavior. Reduced audit quality behavior is a serious threat to the auditing profession. Auditing cases, such as Enron Corporation and Worldcom have made the audit rofession to be the public spotlight, which makes the credibility of the auditors increasingly questionable. This study aimed to examine the factors that can cause reduced audit quality behavior such as time budget pressure, locus of control and professional commitment.  The research used questionnaire that was distributed to 70 auditors of BPKP Representative of Bali Province. Method of determining the sample was saturated sampling. The data analysis was conducted by multiple linear regressions, and the results showed that the time budget pressure and external locus of control has a positive influence on reduced audit quality behavior, while internal locus of control and professional commitment have negative effect.   Keywords:  reduced audit quality behavior, time budget pressure, locus of control, professional commitment

  8. Identification of a novel locus for a USH3 like syndrome combined with congenital cataract

    DEFF Research Database (Denmark)

    Dad, S.; Østergaard, Elsebet; Thykjær, T.

    2010-01-01

    Usher syndrome (USH) is the most common genetic disease that causes both deafness and blindness. USH is divided into three types, USH1, USH2 and USH3, depending on the age of onset, the course of the disease, and on the degree of vestibular dysfunction. By homozygosity mapping of a consanguineous...... Danish family of Dutch descent, we have identified a novel locus for a rare USH3-like syndrome. The affected family members have a unique association of retinitis pigmentosa, progressive hearing impairment, vestibular dysfunction, and congenital cataract. The phenotype is similar, but not identical...... to that of USH3 patients, as congenital cataract has not been reported for USH3. By homozygosity mapping, we identified a 7.3 Mb locus on chromosome 15q22.2-23 with a maximum multipoint LOD score of 2.0. The locus partially overlaps with the USH1 locus, USH1H, a novel unnamed USH2 locus, and the non-syndromic...

  9. Relationships between Locus of Control, Self-Efficacy, Efforts and Academic Achievement among Engineering Students

    Directory of Open Access Journals (Sweden)

    Alias Maizam

    2016-01-01

    Full Text Available The aim of this study is to investigate the relationships between the affective learning needs namely, self-efficacy and locus of control, learning efforts and academic achievement among engineering students. For this purpose, a survey was conducted on first year engineering students from two technical universities in Malaysia. Self-efficacy and locus of control were assessed using existing instruments while learning efforts were assessed using a specifically designed instrument based on Carbonaro’s model of learning effort. Academic achievement data were based on cumulative grade point average (CGPA obtained from self-report by participants. The findings indicate that females engineering students tend to have higher self-efficacy compared to males while both groups have similar locus of control and invest in similar learning efforts. Only locus of control is found to be related to academic achievement while self-efficacy is found to be related to efforts. In conclusion, locus of control seems to be an important factor in predicting academic achievement among engineering students.

  10. Physical Localization of a Locus from Agropyron cristatum Conferring Resistance to Stripe Rust in Common Wheat.

    Science.gov (United States)

    Zhang, Zhi; Song, Liqiang; Han, Haiming; Zhou, Shenghui; Zhang, Jinpeng; Yang, Xinming; Li, Xiuquan; Liu, Weihua; Li, Lihui

    2017-11-13

    Stripe rust, caused by Puccinia striiformis f. sp. tritici ( Pst ), is one of the most destructive diseases of wheat ( Triticum aestivum L.) worldwide. Agropyron cristatum (L.) Gaertn. (2 n = 28, PPPP), one of the wild relatives of wheat, exhibits resistance to stripe rust. In this study, wheat- A . cristatum 6P disomic addition line 4844-12 also exhibited resistance to stripe rust. To identify the stripe rust resistance locus from A . cristatum 6P, ten translocation lines, five deletion lines and the BC₂F₂ and BC₃F₂ populations of two wheat- A . cristatum 6P whole-arm translocation lines were tested with a mixture of two races of Pst in two sites during 2015-2016 and 2016-2017, being genotyped with genomic in situ hybridization (GISH) and molecular markers. The result indicated that the locus conferring stripe rust resistance was located on the terminal 20% of 6P short arm's length. Twenty-nine 6P-specific sequence-tagged-site (STS) markers mapped on the resistance locus have been acquired, which will be helpful for the fine mapping of the stripe rust resistance locus. The stripe rust-resistant translocation lines were found to carry some favorable agronomic traits, which could facilitate their use in wheat improvement. Collectively, the stripe rust resistance locus from A . cristatum 6P could be a novel resistance source and the screened stripe rust-resistant materials will be valuable for wheat disease breeding.

  11. Hybrid male sterility in rice is due to epistatic interactions with a pollen killer locus.

    Science.gov (United States)

    Kubo, Takahiko; Yoshimura, Atsushi; Kurata, Nori

    2011-11-01

    In intraspecific crosses between cultivated rice (Oryza sativa) subspecies indica and japonica, the hybrid male sterility gene S24 causes the selective abortion of male gametes carrying the japonica allele (S24-j) via an allelic interaction in the heterozygous hybrids. In this study, we first examined whether male sterility is due solely to the single locus S24. An analysis of near-isogenic lines (NIL-F(1)) showed different phenotypes for S24 in different genetic backgrounds. The S24 heterozygote with the japonica genetic background showed male semisterility, but no sterility was found in heterozygotes with the indica background. This result indicates that S24 is regulated epistatically. A QTL analysis of a BC(2)F(1) population revealed a novel sterility locus that interacts with S24 and is found on rice chromosome 2. The locus was named Epistatic Factor for S24 (EFS). Further genetic analyses revealed that S24 causes male sterility when in combination with the homozygous japonica EFS allele (efs-j). The results suggest that efs-j is a recessive sporophytic allele, while the indica allele (EFS-i) can dominantly counteract the pollen sterility caused by S24 heterozygosity. In summary, our results demonstrate that an additional epistatic locus is an essential element in the hybrid sterility caused by allelic interaction at a single locus in rice. This finding provides a significant contribution to our understanding of the complex molecular mechanisms underlying hybrid sterility and microsporogenesis.

  12. Lupus risk variants in the PXK locus alter B-cell receptor internalization

    Directory of Open Access Journals (Sweden)

    Samuel E. Vaughn

    2015-01-01

    Full Text Available Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus, rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb common haplotype that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3’ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 x 10-10, OR 0.81 (0.75 – 0.86. Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 200kb.Functionally, we found that PXK operates on the B-cell antigen receptor (BCR; we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.

  13. Multiple-locus variable-number tandem repeat analysis for molecular typing of Aspergillus fumigatus

    Directory of Open Access Journals (Sweden)

    Chermette René

    2010-12-01

    Full Text Available Abstract Background Multiple-locus variable-number tandem repeat (VNTR analysis (MLVA is a prominent subtyping method to resolve closely related microbial isolates to provide information for establishing genetic patterns among isolates and to investigate disease outbreaks. The usefulness of MLVA was recently demonstrated for the avian major pathogen Chlamydophila psittaci. In the present study, we developed a similar method for another pathogen of birds: the filamentous fungus Aspergillus fumigatus. Results We selected 10 VNTR markers located on 4 different chromosomes (1, 5, 6 and 8 of A. fumigatus. These markers were tested with 57 unrelated isolates from different hosts or their environment (53 isolates from avian species in France, China or Morocco, 3 isolates from humans collected at CHU Henri Mondor hospital in France and the reference strain CBS 144.89. The Simpson index for individual markers ranged from 0.5771 to 0.8530. A combined loci index calculated with all the markers yielded an index of 0.9994. In a second step, the panel of 10 markers was used in different epidemiological situations and tested on 277 isolates, including 62 isolates from birds in Guangxi province in China, 95 isolates collected in two duck farms in France and 120 environmental isolates from a turkey hatchery in France. A database was created with the results of the present study http://minisatellites.u-psud.fr/MLVAnet/. Three major clusters of isolates were defined by using the graphing algorithm termed Minimum Spanning Tree (MST. The first cluster comprised most of the avian isolates collected in the two duck farms in France, the second cluster comprised most of the avian isolates collected in poultry farms in China and the third one comprised most of the isolates collected in the turkey hatchery in France. Conclusions MLVA displayed excellent discriminatory power. The method showed a good reproducibility. MST analysis revealed an interesting clustering with a

  14. Two different secondary metabolism gene clusters occupied the same ancestral locus in fungal dermatophytes of the arthrodermataceae.

    Science.gov (United States)

    Zhang, Han; Rokas, Antonis; Slot, Jason C

    2012-01-01

    Dermatophyte fungi of the family Arthrodermataceae (Eurotiomycetes) colonize keratinized tissue, such as skin, frequently causing superficial mycoses in humans and other mammals, reptiles, and birds. Competition with native microflora likely underlies the propensity of these dermatophytes to produce a diversity of antibiotics and compounds for scavenging iron, which is extremely scarce, as well as the presence of an unusually large number of putative secondary metabolism gene clusters, most of which contain non-ribosomal peptide synthetases (NRPS), in their genomes. To better understand the historical origins and diversification of NRPS-containing gene clusters we examined the evolution of a variable locus (VL) that exists in one of three alternative conformations among the genomes of seven dermatophyte species. The first conformation of the VL (termed VLA) contains only 539 base pairs of sequence and lacks protein-coding genes, whereas the other two conformations (termed VLB and VLC) span 36 Kb and 27 Kb and contain 12 and 10 genes, respectively. Interestingly, both VLB and VLC appear to contain distinct secondary metabolism gene clusters; VLB contains a NRPS gene as well as four porphyrin metabolism genes never found to be physically linked in the genomes of 128 other fungal species, whereas VLC also contains a NRPS gene as well as several others typically found associated with secondary metabolism gene clusters. Phylogenetic evidence suggests that the VL locus was present in the ancestor of all seven species achieving its present distribution through subsequent differential losses or retentions of specific conformations. We propose that the existence of variable loci, similar to the one we studied, in fungal genomes could potentially explain the dramatic differences in secondary metabolic diversity between closely related species of filamentous fungi, and contribute to host adaptation and the generation of metabolic diversity.

  15. [BLG gene knockout and hLF gene knock-in at BLG locus in goat by TALENs].

    Science.gov (United States)

    Song, Shaozheng; Zhu, Mengmin; Yuan, Yuguo; Rong, Yao; Xu, Sheng; Chen, Si; Mei, Junyan; Cheng, Yong

    2016-03-01

    To knock out β-lactoglobulin (BLG) gene and insert human lactoferrin (hLF) coding sequence at BLG locus of goat, the transcription activator-like effector nucleases (TALEN) mediated recombination was used to edit the BLG gene of goat fetal fibroblast, then as donor cells for somatic cell nuclear transfer. We designed a pair of specific plasmid TALEN-3-L/R for goat BLG exon III recognition sites, and BLC14-TK vector containing a negative selection gene HSV-TK, was used for the knock in of hLF gene. TALENs plasmids were transfected into the goat fetal fibroblast cells, and the cells were screened three days by 2 μg/mL puromycin. DNA cleavage activities of cells were verified by PCR amplification and DNA production sequencing. Then, targeting vector BLC14-TK and plasmids TALEN-3-L/R were co-transfected into goat fetal fibroblasts, both 700 μg/mL G418 and 2 μg/mL GCV were simultaneously used to screen G418-resistant cells. Detections of integration and recombination were implemented to obtain cells with hLF gene site-specific integration. We chose targeting cells as donor cells for somatic cell nuclear transfer. The mutagenicity of TALEN-3-L/R was between 25% and 30%. A total of 335 reconstructed embryos with 6 BLG-/hLF+ targeting cell lines were transferred into 16 recipient goats. There were 9 pregnancies confirmed by ultrasound on day 30 to 35 (pregnancy rate of 39.1%), and one of 50-day-old fetus with BLG-/hLF+ was achieved. These results provide the basis for hLF gene knock-in at BLG locus of goat and cultivating transgenic goat of low allergens and rich hLF in the milk.

  16. Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1)

    DEFF Research Database (Denmark)

    Knudsen, Nina Østergaard; Nielsen, Finn Cilius; Vinther, Lena

    2007-01-01

    interaction with hMLH1 and we show that defective nuclear localization of hEXO1 mutant proteins could be rescued by hMLH1 or hMSH2. Both hEXO1 and hMLH1 form complexes with the nuclear import factors importin beta/alpha1,3,7 whereas hMSH2 specifically recognizes importin beta/alpha3. Taken together, we infer...... that hEXO1, hMLH1 and hMSH2 form complexes and are imported to the nucleus together, and that redundant NLS import signals in the proteins may safeguard nuclear import and thereby MMR activity....

  17. An unusual occurrence of repeated single allele variation on Y-STR locus DYS458

    Directory of Open Access Journals (Sweden)

    Pankaj Shrivastava

    2016-09-01

    Full Text Available Six brothers were accused of gagging and raping a woman. A single male Y-STR profile was obtained from vaginal smear swab and clothes of the victim, which did not match with the DNA profile of the accused brothers. As a reference point, the blood sample of their father (aged 87 years was also analyzed with the same kit. The Y-STR haplotype of all six brothers was found to be the same as that of their father except at locus DYS458. At this locus, while the eldest, second and fourth siblings share allele 18 with their father, a loss of one repeat (allele 17 instead of 18 is observed in the third son while fifth and sixth siblings have allele 19 representing a gain of one repeat. Thus, two changes viz. a gain (twice and loss of one repeat at this locus in one generation is both interesting and unusual.

  18. Dissection of a locus on mouse chromosome 5 reveals arthritis promoting and inhibitory genes

    DEFF Research Database (Denmark)

    Lindvall, Therese; Karlsson, Jenny; Holmdahl, Rikard

    2009-01-01

    with Eae39 congenic- and sub-interval congenic mice, carrying RIIIS/J genes on the B10.RIII genetic background, revealed three loci within Eae39 that control disease and anti-collagen antibody titers. Two of the loci promoted disease and the third locus was protecting from collagen induced arthritis...... development. By further breeding of mice with small congenic fragments, we identified a 3.2 Megabasepair (Mbp) interval that regulates disease. CONCLUSIONS: Disease promoting- and protecting genes within the Eae39 locus on mouse chromosome 5, control susceptibility to collagen induced arthritis. A disease......-protecting locus in the telomeric part of Eae39 results in lower anti-collagen antibody responses. The study shows the importance of breeding sub-congenic mouse strains to reveal genetic effects on complex diseases....

  19. Note on guilt appeals in advertising: covariate effects of self-esteem and locus of control.

    Science.gov (United States)

    Pinto, M B; Worobetz, N D

    1992-02-01

    A 1991 study by Pinto and Priest demonstrated the effectiveness of advertisements employing moderate levels of guilt in inducing guilt responses in subjects. Because individuals' responses to guilt are often influenced by their specific personality characteristics, researchers have pointed to the potential moderating effects of individual difference variables such as level of self-esteem and locus of control on individuals' susceptibility to guilt appeals. A study was conducted to evaluate the possibility that self-esteem and locus of control can act as covariates across three treatment levels of guilt advertising. From a sample of 57 working mothers, advertisements stimulating medium and high levels of guilt elicited significantly greater feelings of guilt in subjects than the control advertisement stimulating low guilt. However, the relationship between susceptibility to guilt appeals and self-esteem and locus of control was not observed to covary.

  20. Jurors' locus of control and defendants' attractiveness in death penalty sentencing.

    Science.gov (United States)

    Beckham, Crystal M; Spray, Beverly J; Pietz, Christina A

    2007-06-01

    The authors examined the relationship between jurors' locus of control and defendants' attractiveness in death penalty sentencing. Ninety-eight participants voluntarily served as mock jurors. The authors administered J. B. Rotter's (1966) Internal-External Locus of Control Scale to participants and then randomly assigned them to a group with either an attractive or an unattractive defendant (represented by photographs). Participants read a murder vignette and selected a punishment--either a lifetime jail sentence or the death penalty-for the defendant. Results indicated that neither jurors' locus of control nor defendants' attractiveness influenced sentencing. However, jurors' age and gender significantly influenced sentencing. Men, with the exception of the youngest men, were more likely than women to choose the death penalty. Additionally, young women were more likely than older women to select the death penalty. The authors discuss the implications of these results for the study of jury behavior and bias.